U.S. patent number 6,593,344 [Application Number 09/595,547] was granted by the patent office on 2003-07-15 for piperadinyl-substituted pyridylalkane, alkene and alkine carboxamides.
This patent grant is currently assigned to Klinge Pharma GmbH. Invention is credited to Elfi Biedermann, Max Hasmann, Roland Loser, Benno Rattel, Friedemann Reiter, Barbara Schein, Isabel Schemainda, Klaus Seibel, Klaus Vogt, Katja Wosikowski.
United States Patent |
6,593,344 |
Biedermann , et al. |
July 15, 2003 |
Piperadinyl-substituted pyridylalkane, alkene and alkine
carboxamides
Abstract
The invention relates to new piperidinyl-substituted pyridyl
carboxamides of the general formula (I), wherein the structure
element E has meanings (E1) or (E2) and whereby the heterocyclic
ring can optionally have a double bond. These substances have
especially high cytostatic activities and pronounced
immunosuppressive properties which make them suitable for
therapeutic treatment in broad tumor spectrum. ##STR1##
Inventors: |
Biedermann; Elfi (Vaterstetten,
DE), Hasmann; Max (Neuried, DE), Loser;
Roland (Feldafing, DE), Rattel; Benno (Munich,
DE), Reiter; Friedemann (Putzbrunn, DE),
Schein; Barbara (Neufahrn, DE), Seibel; Klaus
(Grafelfing, DE), Vogt; Klaus (Munich, DE),
Wosikowski; Katja (Poing, DE), Schemainda; Isabel
(Munich, DE) |
Assignee: |
Klinge Pharma GmbH (Munich,
DE)
|
Family
ID: |
7852331 |
Appl.
No.: |
09/595,547 |
Filed: |
June 16, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCTEP9808269 |
Dec 16, 1998 |
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Foreign Application Priority Data
|
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Dec 17, 1997 [DE] |
|
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197 56 235 |
|
Current U.S.
Class: |
514/318;
514/231.5; 544/124; 546/193 |
Current CPC
Class: |
A61P
35/02 (20180101); C07D 413/12 (20130101); C07F
9/5532 (20130101); C07D 495/04 (20130101); C07D
403/14 (20130101); C07D 405/14 (20130101); A61P
35/00 (20180101); C07D 491/10 (20130101); C07F
9/65583 (20130101); C07D 471/04 (20130101); C07D
401/14 (20130101); C07D 417/14 (20130101); C07D
471/10 (20130101); A61P 37/00 (20180101); C07F
9/59 (20130101); C07D 401/12 (20130101); C07D
491/04 (20130101); C07D 413/14 (20130101); C07D
409/14 (20130101); C07D 487/08 (20130101) |
Current International
Class: |
C07D
417/14 (20060101); C07D 417/00 (20060101); C07D
413/14 (20060101); C07F 9/553 (20060101); C07F
9/00 (20060101); C07F 9/59 (20060101); C07D
401/12 (20060101); C07D 401/14 (20060101); C07D
401/00 (20060101); C07D 403/00 (20060101); C07D
487/08 (20060101); C07D 495/00 (20060101); C07D
491/04 (20060101); C07D 405/00 (20060101); C07D
471/10 (20060101); C07D 405/14 (20060101); C07D
498/00 (20060101); C07F 9/6558 (20060101); C07D
487/00 (20060101); C07D 471/04 (20060101); C07D
471/00 (20060101); C07D 403/14 (20060101); C07D
413/12 (20060101); C07D 498/10 (20060101); C07D
409/14 (20060101); C07D 413/00 (20060101); C07D
491/00 (20060101); C07D 491/10 (20060101); C07D
409/00 (20060101); C07D 495/04 (20060101); A01N
043/60 (); C07D 211/06 (); C07D 405/00 () |
Field of
Search: |
;514/318,231.5 ;544/124
;546/193 |
References Cited
[Referenced By]
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WO |
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WO95/10514 |
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WO |
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WO95/10515 |
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WO |
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WO |
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WO95/24894 |
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Sep 1995 |
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WO |
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WO |
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Oct 1996 |
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WO |
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WO94/01402 |
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WO |
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WO93/13083 |
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Apr 1997 |
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WO |
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WO97/48397 |
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Dec 1997 |
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WO |
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WO96/31477 |
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Jan 1998 |
|
WO |
|
WO97/48695 |
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Jan 1998 |
|
WO |
|
Other References
Nishikawa et al., "Acrylamide Derivatives as Antiallergic Agents.
2. Synthesis and Structure-Activity Relationships of
N-[4-[4-(Diphenylmethyl)-1-piperazinyl]butyl
]-3-(3-pyridyl)acrylamides" Chem. Pharm. Bull. 37(1) 100-105
(1989). .
Nishikawa et al., "Acrylamide Derivatives as Antiallergic Agents.
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N-[W-[N-Alkyl-N-(phenylmethyl)amino]alkyl]-3-arylpropenamides"
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Rote Liste, 1997..
|
Primary Examiner: Raymond; Richard L
Assistant Examiner: Truong; Tamthom N.
Attorney, Agent or Firm: Fitch, Even, Tabin &
Flannery
Parent Case Text
This is a continuation of prior application number PCT/EP98/08269,
filed Dec. 16, 1998 and designating the U.S., which is hereby
incorporated herein by reference in its entirety.
Claims
What is claimed is:
1. Pyridylalkane, pyridylalkene and pyridylalkine acid amide
compounds of general formula ##STR238##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen,halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR239## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R .sup.2, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of G.sup.1, G.sup.2, G.sup.3,
G.sup.4 and G.sup.5, wherein G.sup.1 is --(CH.sub.2).sub.r
--(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0, 1, 2 or 3 and s is
0 or 1 R.sup.13 is selected from the group consisting of hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or
unsaturated, four to seven-membered heterocycles, which contain one
or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated carbocyclic ring
system with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms ate selected from N,
S and O and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl, saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi- and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, an R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 is selected from ##STR240##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
2. Compounds of general Formula (I), ##STR244##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy,
C.sub.1 -C.sub.4 -alkoxy, benzyloxy, C.sub.1 -C.sub.4 -alkylthio,
C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.2
-C.sub.5 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.5
-alkylaminocarbonyl, C.sub.3 -C.sub.9 -dialkylaminocarbonyl,
carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 are selected independently of
each other from hydrogen and C.sub.1 -C.sub.6 -alkyl, R.sup.2 is
selected from the group consisting of hydrogen, halogen, cyano,
C.sub.1 -C.sub.6 -alkyl, triflurormethyl, hydroxy, and C.sub.1
-C.sub.6 -alkoxy, R.sup.3 is selected from the group consisting of
hydrogen, halogen, and C.sub.1 -C.sub.6 -alkyl, R.sup.4 selected
from the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl,
C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -cycloalkyl, hydroxy,
C.sub.1 -C.sub.6 -alkoxy and benzyloxy, k is 0 or 1, A is selected
from the group consisting of C.sub.2 -C.sub.6 -alkylene, a
substituted C.sub.2 -C.sub.6 -alkylene, which is substituted one to
three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, or SO.sub.2, wherein,
with the exception of CO, the isosteric substitution is not
adjacent to the amide group and R.sup.9 is selected from the group
consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6
-acyl and methanesulfonyl; 1,2-cyclopropylene, C.sub.2 -C.sub.6
-alkenylene, a substituted C.sub.2 -C.sub.6 -alkenylene, which is
substituted one to three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy,
fluorine, cyano or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a
substituted C.sub.4 -C.sub.6 -alkadienylene, which is substituted
once to twice by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or
phenyl, 1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene,
which is substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, or
cyano, and ethinylene D is selected from-the group consisting of
C.sub.2 -C.sub.10 -alkylene, C.sub.2 -C.sub.10 -alkylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl or hydroxy,
C.sub.4 -C.sub.10 -alkenylene, C.sub.4 -C.sub.10 -alkenylene, which
is substituted once or twice by C.sub.1 -C.sub.3 -alkyl or hydroxy,
C.sub.4 -C.sub.10 -alkinylene, C.sub.4 -C.sub.10 -alkinylene, which
is substituted once or twice by C.sub.1 -C.sub.3 -alkyl or hydroxy,
and C.sub.2 -C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or
C.sub.4 -C.sub.10 -alkinylene, wherein one to three methyleneunits
are isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR245## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.ltoreq.4, and q is 1 or 2; R.sup.11 is selected from the group
consisting of hydrogen, C.sub.1 -C.sub.3 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen and an
oxo group adjacent to a nitrogen atom or R.sup.11 and R.sup.12,
together, form a C.sub.1 -C.sub.3 -alkylene bridge under formation
of a bicyclic ring system; G is selected from the group consisting
of G.sup.1, G.sup.2, G.sup.3, G.sup.4 and G.sup.5, wherein G.sup.1
is --(CH.sub.2).sub.r --(CR.sup.14 R.sup.15).sub.s --R.sup.13
wherein r is 0, 1, or 2, s is 0 or 1 and R.sup.13 is selected from
the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.8
-cycloalkyl, benzyl, phenyl, monocyclic aromatic five and
six-membered heterocycles, which contain one to three hetero-atoms
selected from N, S and O and are either bound directly or over a
methylene group, anellated bi- and tricyclic aromatic and partially
hydrogenated carbocyclic ring system with 8 to 16 ring atoms and at
least one aromatic ring, wherein the linkage can occur either over
an aromatic or a hydrogenated ring and either directly or over a
methylene group, and anellated bi- and tricyclic aromatic or
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms can be selected from N, S and O and the linkage can occur
either over an aromatic ring or a hydrogenated ring and either
directly or over a methylene group, R.sup.14 has the same meaning
as R.sup.13, but is selected independently thereof; R.sup.15 is
selected from the group consisting of hydrogen, hydroxy, methyl,
benzyl, phenyl, monocyclic aromatic five and six-membered
heterocycles, which contain one to three hetero-atoms selected from
N, S and O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic and partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrogenated ring and either directly or over a
methylene group, and anellated bi- and tricyclic aromatic and
partially hydrogenated hetertocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms are selected from N, S and O and the linkage can occur either
over an aromatic ring or a hydrogenated ring and either directly or
over a methylene group; G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15
wherein R.sup.13 and R.sup.15 have the above meaning and u is 0 or
1, or u=1, and R.sup.13 and R.sup.15 together with a carbon atom to
which they are attached form a ring selected from the group
consisting of anellated bi- and tricyclic partially hydrated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring and anellated bi- and tricyclic partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein 1 to 3 ring atoms are selected from N, S and
O; or u=0, and R.sup.13 and R.sup.15 together with the carbon atom
C.sub.E of ring E to which they are attached form a ring system
C.sub.E R.sup.13 R.sup.15 selected from the group consisting of
saturated, four to seven-membered heterocycles which contain one or
two hetero-atoms selected from N, S and O, anellated bi- and
tricyclic partially hydrogenated carbocyclic ring systems with 8 to
16 ring atoms and at least one aromatic ring; and anellated bi- and
tricyclic partially hydrogenated heterocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein 1 to 3
ring atoms are selected from N, S and O; G.sup.3 is selected from
the group consisting of ##STR246## wherein r, s and R.sup.13,
R.sup.14, and R.sup.15 have the above meanings, or the group
or ##STR249## wherein r, s and R.sup.13, R.sup.14, and R.sup.15,
Ar.sup.1 and Ar.sup.2 have the above meanings and W is O or S,
wherein the ring systems .dbd.CR.sup.13 R.sup.15 s, --NR.sup.13
R.sup.15 and C.sub.E R.sup.13 R.sup.15 and aromatic ring systems in
the substituents R.sup.1, R.sup.4, R.sup.5, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, Ar.sup.1 and Ar.sup.2 may be
substituted independently from each other by one to three of the
same or different groups selected from the group consisting of
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, benzyloxy, phenoxy,
mercapto, C.sub.1 -C.sub.1 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxyalkyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6 -alkyl)amino and, for
two adjacent residues on the aromatic ring, methylenedioxy, C.sub.1
-C.sub.6 -alkoxy which is entirely or partially substituted by
fluorine, and alkyl-, alkenyl- and cycloalkyl residues in the group
G.sup.1 to G.sup.5 may be substituted by one or two of the same or
different groups selected from the group consisting of hydroxy,
carboxy, C.sub.2 -C.sub.7 -alkoxycarbonyl, benzyloxycarbonyl,
amino, mono-C.sub.1 -C.sub.6 -alkylamino, and di-(C.sub.1 -C.sub.6
-alkyl)amino; their salts, isomers and tautomers.
3. Compounds of general Formula (I) according to claim 3, wherein:
R.sup.1 is selected from the group consisting of hydrogen, halogen,
cyano, methyl, ethyl, trifluoromethyl, hydroxy, C.sub.1 -C.sub.4
-alkoxy, benzyloxy, C.sub.1 -C.sub.5 -alkanoyloxy, methylthio,
ethylthio, methoxycarbonyl, tert-butoxycarbonyl aminocarbonyl,
carboxy, phenoxy, and phenylthio, R.sup.2 is selected from the
group consisting of hydrogen, halogen, trifluromethyl and hydroxy,
R.sup.3 is selected from the group consisting of hydrogen and
halogen, R.sup.4 selected from the group consisting of hydrogen,
C.sub.1 -C.sub.3 -alkyl, allyl, hydroxy and C.sub.1 -C.sub.3
-alkoxy, k is 0 or 1, A is selected from the group consisting of
C.sub.2 -C.sub.6 -alkylene, a substituted C.sub.2 -C.sub.6
-alkylene, which is substituted once or twice by C.sub.1 -C.sub.3
-alkyl, hydroxy and fluorine, C.sub.2 -C.sub.6 -alkylene, wherein a
methylene unit is isosterically replaced by O, S, CO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution
cannot be adjacent to the amide group, C.sub.2 -C.sub.6
-alkenylene, a substituted C.sub.2 -C.sub.6 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.3 -alkyl, hydroxy or
fluorine, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted by C.sub.1 -C.sub.3
-alkyl, or one or two fluorine atoms, 1,3,5-hexatrienylene, and a
substituted 1,3,5-hexatrienylene, which is substituted by fluorine;
D is selected from the group consisting of C.sub.2 -C.sub.8
-alkylene, a substituted C.sub.2 -C.sub.8 -alkylene, which is
substituted once or twice by methyl or hydroxy, C.sub.4 -C.sub.8
-alkenylene, a substituted C.sub.4 -C.sub.8 -alkenylene, which is
substituted once or twice by methyl or hydroxy, C.sub.4 -C.sub.8
-alkinylene, a substituted C.sub.4 -C.sub.8 -alkinylene, which is
substituted once or twice by methyl or hydroxy; and C.sub.2
-C.sub.8 -alkylene, C.sub.4 -C.sub.8 -alkenylene, or C.sub.4
-C.sub.8 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NH, N(CH.sub.3)N(COCH.sub.3),
N(SO.sub.2 CH.sub.3), CO, SO, or S.sub.2 ; E is selected from the
group consisting of ##STR250## wherein the heterocyclic ring may
have a double bond and n and p are independent of each other the
number 0, 1, 2 or 3 where n+p.ltoreq.3, and q is 1 or 2; R.sup.11
is selected from the group consisting of hydrogen, C.sub.1 -C.sub.3
-alkyl, hydroxymethyl, and carboxy, and R.sup.12 is selected from
the group consisting of hydrogen and an oxo group adjacent to a
nitrogen atom G is selected from the group consisting of G.sup.1,
G.sup.2, G.sup.3, G.sup.4 and G.sup.5, wherein G.sup.1 is
--(CH.sub.2).sub.r --(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0,
1 or 2 s is 0 or 1, R.sup.13 is selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.8 -cycloalkyl,
benzyl, phenyl, benzocyclobutyl, indanyl, indenyl, oxoindanyl,
napthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl,
fluroenyl, oxofluorenyl, anthryl, dihydroanthryl oxodihydroanthryl,
dioxodihydroanthryl,phenanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl,
dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl, furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl,
benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl,
indolyl, indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl,
benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl,
oxobenzoisoxazolinyl, benzbthiazolyl, oxobenzothiazolinyl,
benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl,
oxobenzoimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl,
benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl,
oxodihydroimidazopyridyl, thienopyrimidinyl, chromanyl,
chromanonyl, benzopyranyl, chromonyl, quinolyl, isochinolyl,
dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl,
oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl,
naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoiondolyl,
acridinyl, oxodihydroacridinyl, phenanthridinyl,
oxodihydrophenanthridinyl, dihydrobenzoisoquinolinyl,
oxodihydrobenzoisoquinolinyl, phenothiazinyl,
dihydrodibenzooxepinyl, oxodihydrodibenzooxepinyl,
benzocycloptathienyl, oxobenzocycloheptathienyl,
dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl,
dihydrodibenzothiepinyl, oxodihyrodibenzothiepinyl,
octahydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl,
oxodihydrodibenzoazepinyl, octahydrodibenzoazepinyl,
benzocycloheptapyridy, oxobenzocycloheptapyridyl,
oxobenzocycloheptapyridyl, pyridobenzoazepinyl,
dihydropyridobenzoazepinyl, oxodihyrdopyridobenzoazyepinyl,
dihydropyridobenzodiazepinyl, oxodihydropyridobenzodiazepinyl,
dihydrodibenzooxazepinyl, dihydropyridobenzooxazyepinyl,
dihydropyridobenzooxazepinyl, oxodihydropyridobenzooxazepinyl,
dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl,
dihydropyridobenzothiazepinyl and oxodihydropyridobenzothiazepinyl
bound directly or over a methylene group; R.sup.14 has the same
meaning as R.sup.13 but is selected independently thereof; R.sup.15
is selected from the group consisting of hydrogen, hydroxy, methyl,
benzyl, phenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl,
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl,
benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl,
benzothiazolyl, benzimidazolyl, chromanyl, quinolinyl, and
tetrahydroquinolinyl bound directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
indanyl, tetrahydronaphthyl, fluoroenyl, dihydroanthryl,
tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, tetrahydroquinolinyl,
dihydroacridinyl, dihydrodibenzooxepinyl,
dihydrothienobenzothiepinyl, dihyrdodibenzothiepinyl,
dibenzoazepinyl, dihydridibenzoazepinyl, benzocycloheptapyridinyl,
dihydrobenzocycloheptapyridinyl, pyridobenzoazepinyl, and
dihydropyridobenzoazepinyl; or u=0, and R.sup.13 and R.sup.15
together with ring E to which they are attached form a spirocycle
ER.sup.13 R.sup.s15 selected from the group consisting of
dioxaazaspirononane, dithioazaspirononane, oxadiazaspirononane,
oxadiazaspirononandione, triazaspirononane, triazaspirononandione,
diazaspriodecanone, diazaspirodecandione, dioxaazaspirodecane,
dithiaazaspirodecane, oxadiazaspirodecane, triazaspriodecane,
triazaspirodecanone, triazaspirodecandione, dioxaazaspiroundecane,
dithiaazasprioundecane, oxadiazaspiroundecanone,
triazaspiroundecanone, spiro[benzodioxol-pyrrolidine],
spiro[benzodioxolpiperidine], spiro[benzodioxin-piperidine] or
spiro[dihydrobenzoxazin-piperdine]; G.sup.3 is selected from
##STR251## wherein r, s and R.sup.13, R.sup.14 and R.sup.15 can
have the above meanings or the group
4. Compounds of general formula according to claim 3, wherein
R.sup.1 is selected from the group consisting of hydrogen,
fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl,
hydroxy, C.sub.1 -C.sub.4 -alkoxy, methylthio, ethlythio, carboxy
and phenoxy; R.sup.2 is selected from the group consisting of
hydrogen, chlorine and methyl; R.sup.3 is hydrogen; R.sup.4 is
selected from the group consisting of hydrogen, C.sub.1 -C.sub.3
-alkyl and hydroxy; k is 0 A is selected from the group consisting
of C.sub.2 -C.sub.6 -alkylene, a substituted C.sub.2 -C.sub.6
-alkylene, which is substituted once or twice by hydroxy or
fluorine; C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S or CO, wherein, with the exception
of CO, the isosteric substitution cannot be adjacent to the amide
group; C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene which is substituted by C.sub.0 -C.sub.3 -alkyl or
fluorine; and C.sub.4 -C.sub.6 -al kadienylene; D is selected from
the group consisting of C.sub.4 -C.sub.8 -alkylene, a substituted
C.sub.4 -C.sub.8 -alkylene, which is substituted by methyl or
hydroxy, C.sub.4 -C.sub.8 -alkenylene, a substituted C.sub.4
-C.sub.8 -alkenylene, which is substituted by hydroxy, C.sub.4
-C.sub.8 -alkinylene, a substituted C.sub.4 -C.sub.8 -alkinylene,
which is substituted by hydroxy, and C.sub.4 -C.sub.8 -alkylene,
C.sub.4 -C.sub.8 -alkenylene, C.sub.4 -C.sub.8 -alkinylene, wherein
a methylene unit is respectively isosterically replaced by O, NH,
N(CH.sub.3), CO, or SO.sub.2 ; an ethylene group is isosterically
replaced by a group NH--CO or CO--NH or a propylene group is
isosterically replaced bu a group NH--CO--O or O--CO--NH; E is
selected from the group consisting of pyrrolidine, piperidine,
hexahydroazepine or morpholine, wherein the ring may be substituted
by a methyl group or by an oxo group adjacent to a nitrogen atom; G
is methoxycarbonylamino, ethoxycarbonylamino,
tertbutoxycarbonylamino, benzyloxycarbonylamino,
trifluoroacetylamino, diphenylphosphinoylamino,
diphenylphosphinoyloxy, diphenylmethyloxy, or a group selected from
the group consisting of --(CH.sub.2).sub.r --(CR.sup.14
R.sup.15).sub.s --R.sup.13, .dbd.(C).sub.u R.sup.13 R.sup.15,
##STR255## wherein r is 0 or 1, s is 0 or 1, u is 0 or 1, R.sup.13
is selected from the group consisting of hydrogen, methyl, benzyl,
phenyl, indanyl, indenyl, oxoindanyl, napthyl, tetrahydronaphthyl,
fluroenyl, anthryl, phenanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl or oxodihydrodibenzocycloheptenyl,
thienyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, pyridyl,pyrazinyl, pyridazinyl, pyrimidinyl, benzofuryl,
benzothienyl, indolyl, indolinyl, isoindolinyl, oxoindolinyl,
dioxoindolinyl, benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl,
oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl,
benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl,
oxobenzoimidazolinyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, imidazopyridy, oxodihydroimidazopyridyl,
quinolyl, isochinolyl, dihydroquinolinyl, oxodihydroquinolinyl,
tetrahydroquinolinyl, oxotetrahydroquinolinyl, carbazolyl,
tertahydrocarbazolyl, pyridoiondolyl, acridinyl,
oxodihydroacridinyl, phenanthridinyl, dihydrophenanthridinyl,
oxodihydrophenanthridinyl, dihydrobenzoisoquinolinyl,
oxodihydrobenzoisoquinolinyl, phenothiazinyl,
dihydrodibenzooxepinyl, benzocycloptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl,
benzocycloheptapyridy, ocodihydrobenzocycloheptapyridyl,
pyridobenzoazepinyl, dihydropyridobenzoazepinyl,
oxodihyrdopyridobenzoazyepinyl, dihydropyridobenzodiazepinyl,
oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl,
dihydropyridobenzooxazyepinyl, dihydrodibenzothiazepinyl and
dihydropyridobenzothiazepinyl; R.sup.14 is selected from the group
consisting of hydrogen, methyl, benzyl, and phenyl; R.sup.15 is
selected from the group consisting of hydrogen, hydroxy, methyl,
benzyl, phenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl,
furyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,
benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl,
benzothiazolyl, benzimidazolyl, quinolinyl, and
tetrahydroquinolinyl; R.sup.16 is selected from the group
consisting of hydrogen, C.sub.1 -C.sub.4 -alkyl, benzyl, and
phenyl; Ar.sup.1 and Ar.sup.2 are selected independent from each
other from the group consisting of phenyl, pyridyl and naphthyl; or
for u=1, R.sup.13 and R.sup.15 together with a carbon atom
(C).sub.u may form a ring which is selected from the group
consisting of indanyl, tetrahydronaphthyl, fluroenyl,
tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, tetrahydroquinolinyl,
dihydrodibenzooxepinyl, dihydrothi-enobenzothiepinyl,
dihydrodibenzothiepinyl, dibenzoazepi-nyl, dihydrodibenzoazepinyl,
benzocycloheptapyridinyl, dihydrobenzocycloheptapyridinyl,
pyridobenzoazepiyl, dihydropyridobenzoazepinyl, or for u=0,
R.sup.13 and R.sup.15 together with ring E to which they are
attached may form a spirocycle ER.sup.13 R.sup.15 selected from the
group consisting of dioxaazaspirodecane, dithiaaazaspirodecane,
diazaspirodecanone, diazaspirodecandione, triazaspriodecanone,
triazaspirodecandione, dioxaazaspiroundecane,
dithiaazaspiroundecane, oxadiazasprioroundecanone,
triazasprioroundecanone, spiro[benzodioxol-pyrrolidin],
spiro[benzodioxol-piperidine], spiro-[benzodioxin-piperidine], and
spiro [dihydrobenzooxazin-piperidine]; the group NR.sup.13 R.sup.15
represents a heterocyclic ring bound over the nitrogen atom which
heterocycle ring is selected from the group consisting of:
piperidine, hexahydroazepine, piperazine, hexahydroazepine,
morpholine, thiomorpholine, indoline, isoindine,
(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (4H)-dihydrobenzooxazine,
(4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine,
(1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine,
(5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine, carbazole,
(10H)-dihydroacridine, (10H)-dihydrophenanthridine,
(5H)-dibenzoazepine, (5H)-dihydrodibenzoazepine,
(5H)-dihydrodibenzodiazepine, (5H)-benzo[b]pyrido[f]azepine,
(5H)-dihydrobenzo[b]pyrido[f]azepine,
(5H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine,
(11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one and
(11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one, wherein the ring
systems (C).sub.u R.sup.13 R.sup.15, --NR.sup.13 R.sup.15 and
ER.sup.13 R.sup.15 and aromatic ring systems in the substituents
R.sup.1, R.sup.13, R.sup.14, R.sup.15, Ar.sup.1 and Ar.sup.2 may be
substituted independently of each other by one to three of the same
or different groups selected from the group consisting of halogen,
cyano, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkoxy
entirely or partially substituted by benzyloxy, pehnoxy, mercapto,
C.sub.1 -C.sub.6 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6 -alkyl)-amino and, for
two adjacent residues on the aromatic ring, methoylenedioxy, and
wherein alkyl-, alkenyl- and cycloalkyl residues in the groups G
may be substituted by one or two of the same or different groups
selected from the group consisting of hydroxy, carboxy, C.sub.2
-C.sub.7 -alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C.sub.1
-C.sub.6 -alkylamino and di-(C.sub.1 -C.sub.6 -alkyl)-amino.
5. Compounds of general formula (I) according to claim 4, wherein
R.sup.1 is selected from the group consisting of hydrogen,
fluorine, methyl, trifluoromethyl, and ethylthio; R.sup.2, R.sup.3
and R.sup.4 are each hydrogen; k is 0; A is selected from the group
consisting of ethylene, propylene or butylene which may be
substitued by hydroxy or one or two fluorine atoms or OCH.sub.2 or
SCH.sub.2 ; ethylene, and 1,3-butadienylene; D is selected from the
group consisting of C.sub.4 -C.sub.6 -alkylene which may be
substituted by hydroxy; C.sub.4 -C.sub.6 alkenylene; C.sub.4
-C.sub.6 alkinylene; C.sub.1 -C.sub.6 alkylene, C.sub.4 -C.sub.6
alkenylene or C.sub.4 -C.sub.6 alkinylene, wherein one or two
methylene units is isosterically replaced by O, NH, CO or SO.sub.2,
E is piperidine G is selected from the group consisting of
diphenylmethyl, diphenylhydroxymethyl, diphenylmethylene, naphthyl,
tetrahydronaphthyl, tetrahydronaphthylidene, fluoroenyl,
fluorenylidene, tetrahydrobenzocycloheptenyl or
tetrahydrobenzocycloheptenylidene, dihydrodibenzocycloheptenyl,
dihydrodibenzocycloheptenylidene, gem-diphenyl,
phenyl-thienylmethyl, phenyl-thienylmethylene,
phenyl-pyridylmethyl, tetrahydroquinolinyl, tetrahydroisquinolinyl,
benzocycloheptapyridinyl, benzocycloheptapyridinylidene,
dihydrobenzocycloheptapyridinyl,
dihydrobenzocycloheptapyridinylidene, dihydrodibenzooxepinyl,
dihydrodibenzooxepinylidene, dihydrodibenzothiepinyl,
dihydrodibenzothiepinylidene, dihydrobenzothienothiepinyl or
dihydrobenzothienothiepinylidene; indolyl, oxobenzoimidazolyl,
oxobenzothiazolyl, benzoisothiazolyl, benzotriazolyl,
dibenzylaminaocarbonyl, diphenylaminocarbonyl,
indolinyl-N-carbonyl, isoindolinyl-N-carbonyl,
tetrahydroquinolinyl-N-carbonyl,
tetrahydrobenzoazepinyl-N-carbonyl; diphenylmethylamino,
kiphenylmethyl-methylamino, dibenzylamino, benzylphenylamno,
triphenylmenthylamno; acetylamino, pivaloylamino,
phenylacetylamino, diphenylacetylamino, diphenylpropionylamino,
naphtyhylacetylamino, benzoylamino, benzoylmethylamino,
naphthoylamino, oxofluorenylcarbonylamino, furoylamino,
pyridylacetylamino or pyridylcarbonylamino,
benzylaminoscarbonylamino, naphthylmethylaminocarbonylamino,
indanylaminocarbonylamino, tetrahydronaphthylaminocarbonyl,
dibenzylaminocarbonylamino, phenylylaminocarbonylamino,
naphthlaminocarbonylamino, benzylphenylaminocarbonylamino,
diphenylaminocarbonylamino, indolinyl-N-carbonylamino,
isoindolinyl-N-carbonylamino, tetrahydraquinolinyl-N-carbonylamino,
tetrahydrobenzoazepinyl-N-carbonylamino,
carbazolyl-N-carbonylamino, dihydrophenanthridinyl-N-carbonylamino,
dihydrodibenzoazepin-N-carbonylamino,
dihydrobenzopyridoazepinyl-N-carbonylamino,
oxodihydrobenzopyridodiazepinyl-N-carbonylamino,
methanesulfonylamino, tolylsulfonylamino, naphthylsulfonylamino,
diphenylphosphinoylamino, diphenylmethyloxy, and
diphenylphosphinoyloxy, wherein aromatic ring systems may be
substituted independently of each other by one to three of the same
or different groups selected from the group consisting of halogen,
cyano, C.sub.1 -C.sub.6 -Alkyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkoxy
entirely or partially substituted by fluorine, benzyloxy, phenoxy,
mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6 -alkyl)-amino and, for
two adjacent residues on the aromatic ring, methylenedioxy, alkyl-,
alkenyl- and cycloalkyl residues in the group G can be
substitutedby one or two of the same of different groups selected
from the group consisting of hydroxy, carboxy, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C.sub.1 -C.sub.6
-alkylamino, di-(C.sub.1 -C.sub.6,-alkyl)amino; and their salts,
isomers and tautomers.
6. Compounds according to general formula (I) according to claim 5,
selected from the group consisting of
N-[4-(4-phenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide;
N-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-3-pyr
idin-3-yl-acrylamide,
N-[4-(4-benzotruazol-1-yl-piperidin-1-yl]-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(hydroxy-diphenylmethyl)-piperidin-1-yl]-butyl}-2-(pyridin-3-yloxy)
-acetamide;
N-[4-(4,4-diphenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}
-3-pyridin-3-yl-propionamide dihydrochloride/semi-isopropanol;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}
-5-pyridin-3-yl-pentanamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl
]-butyl}-3-pyridin-3-yl-propionamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl
]-butyl}-3-pyridin-3-yl-acrylamide;
N-[4-(4-diphenylphosphinoyloxy-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acryla
mide; and
N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-3-pyridin-3-yl-acrylamide.
7. A pharmaceutical composition comprising a compound of formula
(I) ##STR256##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6,wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.1 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.1 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR257## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.gtoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of G.sup.1, G.sup.2, G.sup.3,
G.sup.4 and G.sup.5, wherein G.sup.1 is --(CH.sub.2).sub.r
--(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0, 1, 2 or 3 and s is
0 or 1 R.sup.13 is selected from the group consisting of hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or
unsaturated, four to seven-membered heterocycles, which contain one
or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated carbocyclic
ringsystem with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and O and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.G R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl, saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected-from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi- and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, and R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 is selected from ##STR258##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
##STR259## --NR.sup.16 --SO.sub.2 --(CH.sub.2).sub.r --R.sup.13
(G4d),
##STR260## and --NR.sup.16 --COR.sup.17 (G4f), wherein r, s and
R.sup.13, R.sup.14, and R.sup.15 have the above meanings and
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; G.sup.5 is selected from the group
consisting of
and ##STR261## wherein r, s, and R.sup.13, R.sup.14, R.sup.15,
Ar.sup.1 and Ar.sup.2 have the above meanings and W is O or S,
wherein the ring systems .dbd.CR.sup.13 R.sup.15, --NR.sup.13
R.sup.15, --C.sub.E R.sup.13 R.sup.15 and aromatic ring systems in
the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, Ar.sup.1 and
Ar.sup.2 may be substituted independenitly from each other by one
to three of the same or different groups selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl, benzyl,
hydroxy, C.sub.1 -C.sub.6 -hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy,
benzyloxy, phenoxy, mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy,
C.sub.2 -C.sub.7 -carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl,
C.sub.2 -C.sub.7 -alkoxycarbonyl, benzyloxyalkyl, nitro, amino,
mono-C.sub.1 -C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6
-alkyl)amino and, for two adjacent residues on the aromatic ring,
methyl enedioxy, and C.sub.1 -C.sub.6 -alkoxy which is entirely or
partially substituted by fluorine, wherein alkyl-, alkenyl- and
cycloalkyl residues in the group G.sup.1 to G.sup.5 may be
substituted by one or two of the same or different groups selected
from hydroxy, carboxy, C.sub.2 -C.sub.7 -alkoxycarbonyl,
benzyloxycarbonyl, amino, mono-C.sub.1 -C.sub.6 -alkylamino, and
di-(C.sub.1 -C.sub.6 -alkyl)amino, wherein G is not --CHR.sup.14
--R.sup.13, --C(OH)R.sup.14 --R.sup.13, .dbd.CR.sup.13 R.sup.15 or
--O--CHR.sup.14 --R.sup.13, in the case when simultaneously
R.sup.13 is hydrogen, alkyl or phenyl substituted by halogen,
alkyl, hydroxy or trifluoromethyl, R.sup.14 and R.sup.15 may be
pyridyl or phenyl substituted with halogen, alkyl, hydroxy or
trifluoromethyl, A is alkylene, which may be substituted with
ethenylene or butadienylene, D is alkylene and E is piperidine
substituted in the 4-position; their cis- and trans-isomers, E- and
Z-isomers, and their racemic or non-racemic mixtures, their pure
endo- and exoisomers and mixtures thereof; their respective
tautomers, the corresponding acid addition salts, hydrates and
solvates.
8. The pharmaceutical composition of claim 7 further comprising
ingredients selected from the group consisting of a
pharmaceutically acceptable carrier, toxicologically safe
adjuvants, other active ingredients, and mixtures thereof.
9. The pharmaceutical composition of claim 7 which is present in a
form selected from the group consisting of solid, peroral
administrable form as a tablet, capsule, coated tablet, sustained
action or gastric juice-resistant preparation, peroral
administrable solution, suspension, effervescent tablet, tabs,
sachets, and sustained action form.
10. The pharmaceutical composition of claim 7 which is present in a
form selected from the group consisting of a suitable injection or
infusion preparation together with suitable pharmaceutically
acceptable carriers and adjuvants, a sustained action form, as a
parenteral depot medicinal form, implant, a concentrate, powder,
and lyophilisate.
11. The pharmaceutical composition of claim 7 which is present in a
form selected from the group consisting of an inhalation
therapeutic agent and a spray together with suitable
pharmaceutically acceptable propellants, carriers and
adjuvants.
12. The pharmaceutical composition of claim 7 which is present in
the form of a transdermal therapeutic system for systemic
treatment.
13. The pharmaceutical composition of claim 7 which is present in
the form of a gastrointestinal therapeutic system (GITS) for
systemic treatment.
14. The pharmaceutical composition of claim 7 which is present in a
form selected from the group consisting of a salve, suspension,
emulsion, a balm, plaster, and an externally applicable
solution.
15. The pharmaceutical composition of claim 7 which is present in a
form selected from the group consisting of a rectal, genital,
transurethal administrable emulsion, a solution, a liposomal
solution, an implant, suppository, and a capsule.
16. The pharmaceutical composition of claim 7 which is present in
the form selected from the group consisting of a composition
capable of being applied nasally, otologically, and
opthalmologically.
17. The pharmaceutical composition of claim 7 which is present in
the form of a buccally applicable form.
18. The pharmaceutical composition of claim 7 wherein a dosage unit
for single administration contains about 0.001 to about 5000 mg
active ingredient.
19. The pharmaceutical composition of claim 18 wherein a dosage
unit for a single administration contains about 0.01 to about 100
mg active ingredient.
20. The pharmaceutical composition of claim 18 wherein a dosage
unit for a single administration contains about 1 to about 10 mg
active ingredient.
21. A method of inhibiting tumor cell growth in a human or animal
body comprising administering to the human or animal body in need
thereof an amount of a pharmaceutical composition effective for
inhibiting tumor cell growth, wherein the pharmaceutical
composition includes a compound of general formula (I)
##STR262##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sup.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR263## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.gtoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of G.sup.1, G.sup.2, G.sup.3,
G.sup.4 and G.sup.5, wherein G.sup.1 is --(CH.sub.2).sub.r
--(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0, 1, 2 or 3 and s is
0 or 1 R.sup.13 is selected from the group consisting of hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or
unsaturated, four to seven-membered heterocycles, which contain one
or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated carbocyclic ring
system with 8 to 16 ring atoms and at least; one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and O and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi-and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, and R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 is selected from ##STR264##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
--NR.sup.13 R.sup.15 is a nitrogen containing heterocycle bound
over the nitrogen atom which nitrogen-containing heterocycle is
selected from the group consisting of saturated and unsaturated
monocyclic, four to eight-membered heterocycles which, aside from
the essential nitrogen atom, may contain one or two further
hetero-atoms selected from N, S and O, and saturated and
unsaturated bi- or tricyclic, anellated or bridges heterocycles
with 8 to 16 ring atoms, which, aside from the essential nitrogen
atom, may contain one or two further hetero-atoms selected from N,
S and O, G.sup.4 is selected from the group consisting of
##STR265## --NR.sup.16 --SO.sub.2 --(CH.sub.2).sub.r --R.sup.13
(G4d),
##STR266## and --NR.sup.16 --COR.sup.17 (G4f), wherein r, s and
R.sup.13, R.sup.14, and R.sup.15 have the above meanings and
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; G.sup.5 is selected from the group
consisting of
22. A method of suppressing autoimmune diseases in a human or
animal body comprising administering to the human or animal body in
need thereof an amount of a pharmaceutical composition effective
for suppressing autoimmune reactions, wherein the pharmaceutical
composition includes a compound of general formula (I)
##STR268##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.1 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sup.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR269## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.gtoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of G.sup.1, G.sup.2, G.sup.3,
G.sup.4, and G.sup.5, wherein G.sup.1 is --(CH.sub.2).sub.r
--(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0, 1, 2 or 3 and s is
0 or 1 R.sup.13 is selected from the group consisting of hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or
unsaturated, four to seven-membered heterocycles, which contain one
or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially, hydrogenated carbocyclic ring
system with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and O and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl, saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi-and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, and R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 is selected from ##STR270##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
##STR271## --NR.sup.16 --SO.sub.2 --(CH.sub.2).sub.r --R.sup.13
(G4d),
##STR272## and --NR.sup.16 COR.sup.17 (G4f), wherein r, s and
R.sup.13, R.sup.14, and R.sup.15 have the above meanings and
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; G.sup.5 is selected from the group
consisting of
23. A method for production of compounds according to formula (I)
##STR274##
wherein compounds of a formula ##STR275## are reacted with free
base or acid addition salts of formula(III) ##STR276## wherein
R.sup.1 is selected from the group consisting of hydrogen, halogen,
cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl,
C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy,
C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6 -alkinyloxy,
benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2 -C.sub.7
-alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3 -C.sub.6
-alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3 -C.sub.8
-cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2 -C.sub.7
-alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7 -alkoxycarbonyl,
C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
phenylthio, pyridyloxy, pyridylthio, and NR.sup.5 R.sup.6, wherein
R.sup.5 and R.sup.6 selected independently of each other from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, benzyl and phenyl;
R.sup.2 is selected from the group consisting of hydrogen, halogen,
cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7 -alkanoyloxy;
R.sup.1 and R.sup.2, if adjacent, may form a bridge selected from
--(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and --CH.sub.2
O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8 are selected
independently from each other from hydrogen and C.sub.1 -C.sub.6
-alkyl; R.sup.3 is selected from the group consisting of hydrogen,
halogen, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl and C.sub.1
-C.sub.6 -hydroxyalkyl; R.sup.4 selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.6 -cycloalkyl, hydroxy,
C.sub.1 -C.sub.6 -alkoxy and benzyloxy; k is 0 or 1, A is selected
from the group consisting of C.sub.1 -C.sub.6 -alkylene a
substituted C.sub.1 -C.sub.6 -alkylene, which is substituted one to
three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3
-alkoxy, fluorine, or phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a
methylene unit is isosterically replaced by O, S, NR.sup.9, CO, SO,
or SO.sub.2, wherein, with the exception of CO, the isosteric
substitution is not adjacent to the amide group and R.sup.9 is
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.1 -C.sub.6 -acyl and C.sub.1 -C.sub.6 -alkanesulfonyl,
1,2-cyclopropylene, C.sub.2 -C.sub.6 -alkenylene, a substituted
C.sub.2 -C.sub.6 -alkenylene, which is substituted one to
three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6
-alkoxy, fluorine, cyano or phenyl, C.sub.4 -C.sub.6
-alkadienylene, a substituted C.sub.4 -C.sub.6 -alkadienylene,
which is substituted once to twice by C.sub.1 -C.sub.3 -alkyl,
fluorine, cyano or phenyl, 1,3,5-hexatrienylene, a substituted
1,3,5-hexatrienylene, which is substituted by C.sub.1 -C.sub.3
-alkyl, fluorine, cyano or phenyl, and ethinylene D is selected
from the group consisting of C.sub.2 -C.sub.10 -alkylene, a
substituted C.sub.2 -C.sub.10 -alkylene, which is substituted once
or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy, C.sub.4 -C.sub.10 -alkenylene, a substituted C.sub.4
-C.sub.10 -alkenylene, which is substituted once or twice by
C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy,
C.sub.4 -C.sub.10 -alkinylene, a substituted C.sub.4 -C.sub.10
-alkinylene, which is substituted once or twice by C.sub.1 -C.sub.6
-alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy, and C.sub.2 -C.sub.10
-alkylene, C.sub.2 -C.sub.10 -alkylene, C.sub.4 -C.sub.10
-alkenylene, or C.sub.4 -C.sub.10 -alkinylene, wherein one to three
methylene units are isosterically replaced by O, S, NR.sup.10, CO,
SO, or SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9,
but is selected independently thereof; E is selected from the group
consisting of ##STR277## wherein the heterocyclic ring may have a
double bond and n and p are, independent of each other, 0, 1, 2 or
3 where n+p.gtoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected
from the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl,
hydroxy, hydroxymethyl, carboxy, and C.sub.2 -C.sub.7
-alkoxycarbonyl and R.sup.12 is selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl and an oxo group adjacent to a
nitrogen atom, or R.sup.11 and R.sup.12, may together, form a
C.sub.1 -C.sub.3 -alkylene bridge under formation of a bicyclic
ring system; G is selected from the group consisting of G.sup.1,
G.sup.2, G.sup.3, G.sup.4 and G.sup.5, wherein G.sup.1 is
--(CH.sub.2).sub.r --(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0,
1, 2 or 3 and s is 0 or 1 R.sup.13 is selected from the group
consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6
-alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl,
saturated or unsaturated, four to seven-membered heterocycles,
which contain one or two hetero-atoms selected from N, S and O,
benzyl, phenyl, monocyclic aromatic five and six-membered
heterocycles, which contain one to three hetero-atoms selected from
N, S and O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic and partially hydrogenated
carbocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage occurs either over an aromatic
or a hydrogenated ring and either directly or over a methylene
group, and anellated bi- and tricyclic aromatic or partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O and the linkage occurs either over an
aromatic ring or a hydrogenated ring andeither directly or over a
methylene group, R.sup.14 has the same meaning as R.sup.13, but is
selected independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl, saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi-and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, and R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 s selected from ##STR278##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
--NR.sup.13 R.sup.15 is a nitrogen containing heterocycle bound
over the nitrogen atom which nitrogen-containing heterocycle is
selected from the group consisting of saturated and unsaturated
monocyclic, four to eight-membered heterocycles which, aside from
the essential nitrogen atom, may contain one or two further
hetero-atoms selected from N, S and O, and saturated and
unsaturated bi- or tricyclic, anellated or bridges heterocycles
with 8 to 16 ring atoms, which, aside from the essential nitrogen
atom, may contain one or two further hetero-atoms selected from N,
S and O, G.sup.4 is selected from the group consisting of
##STR279## --NR.sup.16 --SO.sub.2 --(CH.sub.2).sub.r --R.sup.13
(G4d),
##STR280## and --NR.sup.16 --COR.sup.17 (G4f), wherein r, s and
R.sup.13, R.sup.14, and R.sup.15 have the above meanings and
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; G.sup.5 is selected from the group
consisting of
24. A method for production of compounds according to
##STR282##
wherein compounds of a formula ##STR283## are reacted with
compounds of formulas (IVa) to (IVe), wherein (IVa) to (IVe) are
##STR284## wherein L is a leaving group and wherein R.sup.1 is
selected from the group consisting of hydrogen, halogen, cyano,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl,
C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy,
C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6 -alkinyloxy,
benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2 -C.sub.7
-alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3 -C.sub.6
-alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3 -C.sub.8
-cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2 -C.sub.7
-alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7 -alkoxycarbonyl,
C.sub.3 -C.sub.3 -dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
phenylthio, pyridyloxy, pyridylthio, and NR.sup.5 R.sup.6, wherein
R.sup.5 and R.sup.6 selected independently of each other from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, benzyl and phenyl;
R.sup.2 is selected from the group consisting of hydrogen, halogen,
cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7 -alkanoyloxy;
R.sup.1 and R.sup.2, if adjacent, may form a bridge selected from
--(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and --CH.sub.2
O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8 are selected
independently from each other from hydrogen and C.sub.1 -C.sub.6
-alkyl; R.sup.3 is selected from the group consisting of hydrogen,
halogen, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl and C.sub.1
-C.sub.6 -hydroxyalkyl; R.sup.4 selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.6 -cycloalkyl, hydroxy,
C.sub.1 -C.sub.6 -alkoxy and benzyloxy; k is 0 or 1, A is selected
from the group consisting of C.sub.1 -C.sub.6 -alkylene a
substituted C.sub.1 -C.sub.6 -alkylene, which is substituted one to
three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3
-alkoxy, fluorine, or phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a
methylene unit is isosterically replaced by O, S, NR.sup.9, CO, SO,
or SO.sub.2, wherein, with the exception of CO, the isosteric
substitution is not adjacent to the amide group and R.sup.9 is
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.1 -C.sub.6 -acyl and C.sub.1 -C.sub.6 -alkanesulfonyl,
1,2-cyclopropylene, C.sub.2 -C.sub.6 -alkenylene, a substituted
C.sub.2 -C.sub.6 -alkenylene, which is substituted one to
three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6
-alkoxy, fluorine, cyano or phenyl, C.sub.4 -C.sub.6
-alkadienylene, a substituted C.sub.4 -C.sub.6 -alkadienylene,
which is substituted once to twice by C.sub.1 -C.sub.3 -alkyl,
fluorine, cyano or phenyl, 1,3,5-hexatrienylene, a substituted
1,3,5-hexatrienylene, which is substituted by C.sub.1 -C.sub.3
-alkyl, fluorine, cyano or phenyl, and ethinylene D is selected
from the group consisting of C.sub.2 -C.sub.10 -alkylene, a
substituted C.sub.2 -C.sub.10 -alkylene, which is substituted once
or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy, C.sub.4 -C.sub.10 -alkenylene, a substituted C.sub.4
-C.sub.10 -alkenylene, which is substituted once or twice by
C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy,
C.sub.4 -C.sub.10 -alkinylene, a substituted C.sub.4 -C.sub.10
-alkinylene, which is substituted once or twice by C.sub.1 -C.sub.6
-alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy, and C.sub.2 -C.sub.10
-alkylene, C.sub.2 -C.sub.10 -alkylene, C.sub.4 -C.sub.10
-alkenylene, or C.sub.4 -C.sub.10 -alkinylene, wherein one to three
methylene units are isosterically replaced by O, S, NR.sup.10, CO,
SO, or SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9,
but is selected independently thereof; E is selected from the group
consisting of ##STR285## wherein the heterocyclic ring may have a
double bond and n and p are, independent of each other, 0, 1, 2 or
3 where n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected
from the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl,
hydroxy, hydroxymethyl, carboxy, and C.sub.2 -C.sub.7
-alkoxycarbonyl and R.sup.12 is selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl and an oxo group adjacent to a
nitrogen atom, or R.sup.11 and R.sup.12, may together, form a
C.sub.1 -C.sub.3 -alkylene bridge under formation of a bicyclic
ring system; G is selected from the group-consisting of ##STR286##
--NR.sup.16 --SO.sub.2 --(CH.sub.2).sub.r R.sup.13 (G4d)
##STR287## r is 0, 1, 2 or 3 and s is 0 or 1 R.sup.13 is selected
from the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl,
C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.3
-C.sub.8 -cycloalkyl, saturated or unsaturated, four to
seven-membered heterocycles, which contain one or two hetero-atoms
selected from N, S and O, benzyl, phenyl, monocyclic aromatic five
and six-membered heterocycles, which contain one to three
hetero-atoms selected from N, S and O and are either bound directly
or over a methylene group, anellated bi- and tricyclic aromatic and
partially hydrogenated carbocyclic ring system with 8 to 16 ring
atoms and at least one aromatic ring, wherein the linkage occurs
either over an aromatic or a hydrogenated ring and either directly
or over a methylene group, and anellated bi- and tricyclic aromatic
or partially hydrogenated heterocyclic ring systems with 8 to 16
ring atoms and at least one aromatic ring, wherein one to three
ring atoms are selected from N, S and O and the linkage occurs
either over an aromatic ring or a hydrogenated ring and either
directly or over a methylene group, R.sup.14 has the same meaning
as R.sup.13, but is selected independently thereof; R.sup.15 is
selected from the group consisting of hydrogen, hydroxy, methyl,
benzyl, phenyl, monocyclic aromatic five and six-membered
heterocycles, which contain one to three hetero-atoms selected from
N, S and O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrogenated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage occurs either over an aromatic
or a hydrogenated ring and either directly or over a methylene
group, anellated bi- and tricyclic aromatic and partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O and the linkage can occur either over an
aromatic ring or a hydrogenated ring and either directly or over a
methylene group; R.sup.16 has the same meanings as R.sup.5, but is
selected independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; wherein aromatic ring systems in the
substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, Ar.sup.1 and
Ar.sup.2 may be substituted independently from each other by one to
three of the same or different groups selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl, benzyl,
hydroxy, C.sub.1 -C.sub.6 -hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy,
benzyloxy, phenoxy, mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy,
C.sub.2 -C.sub.7 -carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl,
C.sub.2 -C.sub.7 -alkoxycarbonyl, benzyloxyalkyl, nitro, amino,
mono-C.sub.1 -C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6
-alkyl)amino and, for two adjacent residues on the aromatic ring,
methylenedioxy, and C.sub.1 -C.sub.6 -alkoxy which is entirely or
partially substituted by fluorine.
25. A method for production of compounds according to formula (I)
##STR288##
where G is --NR.sup.16 --(CH.sub.2).sub.r (CR.sup.14
R.sup.15).sub.s --R.sup.13 but not --NHR.sup.16,
wherein compounds of a formula ##STR289## are reacted with
compounds of formula ##STR290## wherein L is a leaving group,
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR291## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of, hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12 may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system;
R.sup.13 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6
-alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or unsaturated,
four to seven-membered heterocycles, which contain one or two
hetero-atoms selected from N, S and O, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic and partially hydrogenated carbocyclic ring system with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, and anellated bi- and
tricyclic aromatic or partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage occurs either over an aromatic ring or a hydrogenated
ring and either directly or over a methylene group, R.sup.14 has
the same meaning as R.sup.13, but is selected independently
thereof; R.sup.15 is selected from the group consisting of
hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic aromatic five
and six-membered heterocycles, which contain one to three
hetero-atoms selected from N, S and O and are either bound directly
or over a methylene group, anellated bi- and tricyclic aromatic or
partially hydrogenated carbocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein the linkage occurs
either over an aromatic or a hydrogenated ring and either directly
or over a methylene group, anellated bi- and tricyclic aromatic and
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms are selected from N, S and O and the linkage can occur either
over an aromatic ring or a hydrogenated ring and either directly or
over a methylene group; R.sup.16 has the same meanings as R.sup.5,
but is selected independently thereof, R.sup.17 is selected from
the group consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy,
C.sub.3 -C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and
Ar.sup.2, are selected independently from each other from the group
consisting of phenyl, pyridyl and naphthyl; wherein aromatic ring
systems in the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, Ar.sup.1
and Ar.sup.2 may be substituted independently from each other by
one to three of the same or different groups selected from the
group consisting of halogen, cyano, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl, benzyl,
hydroxy, C.sub.1 -C.sub.6 -hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy,
benzyloxy, phenoxy, mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy,
C.sub.2 -C.sub.7 -carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl,
C.sub.2 -C.sub.7 -alkoxycarbonyl, benzyloxyalkyl, nitro, amino,
mono-C.sub.1 -C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6
-alkyl)amino and, for two adjacent residues on the aromatic ring,
methylenedioxy, and C.sub.1 -C.sub.6 -alkoxy which is entirely or
partially substituted by fluorine.
26. A method for production of compounds according to formula (I)
##STR292##
wherein compounds of a formula ##STR293## are reacted with a
carboxylic acid, carbamic acid, sulfonic acid or phosphinic acid of
formulas (Vb) to (Ve), wherein (Vb) to (Ve) are
--HOOC--(CH.sub.2).sub.r --(CR.sup.14 R.sup.15).sub.s --R.sup.13
(Vb),
##STR294## wherein R.sup.1 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6
-alkenyl, C.sub.1 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy,
C.sub.1 -C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3
-C.sub.6 -alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy,
C.sub.2 -C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio,
C.sub.3 -C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio,
C.sub.3 -C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio,
C.sub.2 -C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.1 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
isosterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR295## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of ##STR296## --NR.sup.16
--SO.sub.2 --(CH.sub.2).sub.r --R.sup.13 (G4d), ##STR297## wherein
r is 0, 1, 2 or 3 and s is 0 or 1 R.sup.13 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.8
-cycloalkyl, saturated or unsaturated, four to seven-membered
heterocycles, which contain one or two hetero-atoms selected from
N, S and O, benzyl, phenyl, monocyclic aromatic five and
six-membered heterocycles, which contain one to three hetero-atoms
selected from N, S and O and are either bound directly or over a
methylene group, anellated bi- and tricyclic aromatic and partially
hydrogenated carbocyclic ring system with 8 to 16 ring atoms and at
least one aromatic ring, wherein the linkage occurs either over an
aromatic or a hydrogenated ring and either directly or over a
methylene group, and anellated bi- and tricyclic aromatic or
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms are selected from N, S and O and the linkage occurs either
over an aromatic ring or a hydrogenated ring and either directly or
over a methylene group, R.sup.14 has the same meaning as R.sup.13,
but is selected independently thereof; R.sup.15 is selected from
the group consisting of hydrogen, hydroxy, methyl, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic or partially hydrogenated carbocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic and partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and O and the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; wherein aromatic ring systems in the
substituents R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, Ar.sup.1 and Ar.sup.2 may
be substituted independently from each other by one to three of the
same or different groups selected from the group consisting of
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, benzyloxy, phenoxy,
mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxyalkyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6 -alkyl)amino and, for
two adjacent residues on the aromatic ring, methylenedioxy, and
C.sub.1 -C.sub.6 -alkoxy which is entirely or partially substituted
by fluorine.
27. A method for production of compounds according to formula (I)
##STR298##
where G is ##STR299## wherein compounds of a formula ##STR300## are
reacted with
H--NR.sup.13 R.sup.15 (VI) wherein R.sup.1 is selected from the
group consisting of hydrogen, halogen, cyano, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, C.sub.1 -C.sub.6
-hydroxyalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, C.sub.3 -C.sub.6
-alkenyloxy, C.sub.3 -C.sub.6 -alkinyloxy, benzyloxy, C.sub.1
-C.sub.7 -alkanoyloxy, C.sub.2 -C.sub.7 -alkoxycarbonyloxy, C.sub.1
-C.sub.6 -alkylthio, C.sub.3 -C.sub.6 -alkenylthio, C.sub.3
-C.sub.6 -alkinylthio, C.sub.3 -C.sub.8 -cycloalkyloxy, C.sub.3
-C.sub.8 -cycloalkylthio, C.sub.2 -C.sub.7 -alkoxycarbonyl,
aminocarbonyl, C.sub.2 -C.sub.7 -alkoxycarbonyl, C.sub.3 -C.sub.13
-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio,
pyridyloxy, pyridylthio, and NR.sup.5 R.sup.6, wherein R.sup.5 and
R.sup.6 selected independently of each other from the group
consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6
-alkenyl, C.sub.3 -C.sub.6 -alkinyl, benzyl and phenyl; R.sup.2 is
selected from the group consisting of hydrogen, halogen, cyano,
C.sub.1 -C.sub.6 -alkyl, triflurormethyl, hydroxy, C.sub.1 -C.sub.6
-alkoxy, benzyloxy and C.sub.1 -C.sub.7 -alkanoyloxy; R.sup.1 and
R.sup.2, if adjacent, may form a bridge selected from
--(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and --CH.sub.2
O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8 are selected
independently from each other from hydrogen and C.sub.1 -C.sub.6
-alkyl; R.sup.3 is selected from the group consisting of hydrogen,
halogen, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl and C.sub.1
-C.sub.6 -hydroxyalkyl; R.sup.4 selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.6 -cycloalkyl, hydroxy,
C.sub.1 -C.sub.6 -alkoxy and benzyloxy; k is 0 or 1, A is selected
from the group consisting of C.sub.1 -C.sub.6 -alkylene a
substituted C.sub.1 -C.sub.6 -aalkylene, which is substituted one
to three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3
-alkoxy, fluorine, or phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a
methylene unit is isosterically replaced by O, S, NR.sup.9, CO, SO,
or SO.sub.2, wherein, with the exception of CO, the isosteric
substitution is not adjacent to the amide group and R.sup.9 is
selected from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.1 -C.sub.6 -acyl and C.sub.1 -C.sub.6 -alkanesulfonyl,
1,2-cyclopropylene, C.sub.2 -C.sub.6 -alkenylene, a substituted
C.sub.2 -C.sub.6 -alkenylene, which is substituted one to
three-fold by C.sub.1 -C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6
-alkoxy, fluorine, cyano or phenyl, C.sub.4 -C.sub.6
-alkadienylene, a substituted C.sub.4 -C.sub.6 -alkadienylene,
which is substituted once to twice by C.sub.1 -C.sub.3 -alkyl,
fluorine, cyano or phenyl, 1,3,5-hexatrienylene, a substituted
1,3,5-hexatrienylene, which is substituted by C.sub.1 -C.sub.3
-alkyl, fluorine, cyano or phenyl, and ethinylene D is selected
from the group consisting of C.sub.2 -C.sub.10 -alkylene, a
substituted C.sub.2 -C.sub.10 -alkylene, which is substituted once
or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy, C.sub.4 -C.sub.10 -alkenylene, a substituted C.sub.4
-C.sub.10 -alkenylene, which is substituted once or twice by
C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy,
C.sub.4 -C.sub.10 -alkinylene, a substituted C.sub.4 -C.sub.10
-alkinylene, which is substituted once or twice by C.sub.1 -C.sub.6
-alkyl, hydroxy, or C.sub.1 -C.sub.6 -alkoxy, and C.sub.2 -C.sub.10
-alkylene, C.sub.2 -C.sub.10 -alkylene, C.sub.4 -C.sub.10
-alkenylene, or C.sub.4 -C.sub.10 -alkinylene, wherein one to three
methylene units are isosterically replaced by O, S, NR.sup.10, CO,
SO, or SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9,
but is selected independently thereof; E is selected from the group
consisting of ##STR301## wherein the heterocyclic ring may have a
double bond and n and p are, independent of each other, 0, 1, 2 or
3 where n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected
from the group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl,
hydroxy, hydroxymethyl, carboxy, and C.sub.2 -C.sub.7
-alkoxycarbonyl and R.sup.12 is selected from the group consisting
of hydrogen, C.sub.1 -C.sub.6 -alkyl and an oxo group adjacent to a
nitrogen atom, or R.sup.11 and R.sup.12 may together, form a
C.sub.1 -C.sub.3 -alkylene bridge under formation of a bicyclic
ring system; R.sup.13 is selected from the group consisting of
hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated
or unsaturated, four to seven-membered heterocycles, which contain
one or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated carbocyclic ring
system with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and Q and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and atleast one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
R.sup.16 has the same meanings as R.sup.5, but is selected
independently thereof, R.sup.17 is selected from the group
consisting of trifluoromethyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy and benzyloxy; and Ar.sup.1 and Ar.sup.2, are
selected independently from each other from the group consisting of
phenyl, pyridyl and naphthyl; wherein aromatic ring systems in the
substituents R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, Ar.sup.1 and Ar.sup.2 may
be substituted independently from each other by one to three of the
same or different groups selected from the group consisting of
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, benzyloxy, phenoxy,
mercapto, C.sub.1 -C.sub.6 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxyalkyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, di-(C.sub.1 -C.sub.6 -alkyl)amino and, for
two adjacent residues on the aromatic ring, methylenedioxy, and
C.sub.1 -C.sub.6 -alkoxy which is entirely or partially substituted
by fluorine.
28. A method for production of compounds according to formula (I)
##STR302##
where G is ##STR303## wherein compounds of formula ##STR304## are
reacted with an isocyanate having the formula
29. A method of inhibiting tumor cell growth in a human or animal
body, wherein the tumor cells are selected from the group
consisting of liver tumors, lung carcinomas, rhabdomyosaromcomas,
kidney clear cell carcinoma, colon carcinoma, prostrate carcinoma,
ER positive mamma carcinoma, small cell lung carcinoma,
osteosarcoma, malignant melanoma, ER, PgR positive mamma carcinoma,
glioblastoma, astrocytoma, retinoblastoma, Burkiff's lymphoma,
myeloma, and combinations thereof, the method comprising
administering to the human or animal body in need thereof an amount
of a pharmaceutical composition effective for inhibiting tumor cell
growth, wherein the pharmaceutical composition includes a compound
of general formula (I) ##STR306##
wherein R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, trifluoromethyl, C.sub.3 -C.sub.8
-cycloalkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy, C.sub.3 -C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6
-alkinyloxy, benzyloxy, C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2
-C.sub.7 -alkoxycarbonyloxy, C.sub.1 -C.sub.6 -alkylthio, C.sub.3
-C.sub.6 -alkenylthio, C.sub.3 -C.sub.6 -alkinylthio, C.sub.3
-C.sub.8 -cycloalkyloxy, C.sub.3 -C.sub.8 -cycloalkylthio, C.sub.2
-C.sub.7 -alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, C.sub.3 -C.sub.13 -dialkylaminocarbonyl, carboxy,
phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR.sup.5
R.sup.6, wherein R.sup.5 and R.sup.6 selected independently of each
other from the group consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
benzyl and phenyl; R.sup.2 is selected from the group consisting of
hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl, triflurormethyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and C.sub.1 -C.sub.7
-alkanoyloxy; R.sup.1 and R.sup.2, if adjacent, may form a bridge
selected from --(CH.sub.2).sub.4 --, --(CH.dbd.CH).sub.2 -- and
--CH.sub.2 O--CR.sup.7 R.sup.8 --O--, wherein R.sup.7 and R.sup.8
are selected independently from each other from hydrogen and
C.sub.1 -C.sub.6 -alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4
selected from thegroup consisting of hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy and
benzyloxy; k is 0 or 1, A is selected from the group consisting of
C.sub.1 -C.sub.6 -alkylene a substituted C.sub.1 -C.sub.6
-alkylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.3 -alkoxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO, or SO.sub.2,
wherein, with the exception of CO, the isosteric substitution is
not adjacent to the amide group and R.sup.9 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1 -C.sub.6
-acyl and C.sub.1 -C.sub.6 -alkanesulfonyl, 1,2-cyclopropylene,
C.sub.2 -C.sub.6 -alkenylene, a substituted C.sub.2 -C.sub.6
-alkenylene, which is substituted one to three-fold by C.sub.1
-C.sub.6 -alkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, fluorine, cyano
or phenyl, C.sub.4 -C.sub.6 -alkadienylene, a substituted C.sub.4
-C.sub.6 -alkadienylene, which is substituted once to twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, a substituted 1,3,5-hexatrienylene, which is
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl,
and ethinylene D is selected from the group consisting of C.sub.2
-C.sub.10 -alkylene, a substituted C.sub.2 -C.sub.10 -alkylene,
which is substituted once or twice by C.sub.1 -C.sub.6 -alkyl,
hydroxy, or C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10
-alkenylene, a substituted C.sub.4 -C.sub.10 -alkenylene, which is
substituted once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or
C.sub.1 -C.sub.6 -alkoxy, C.sub.4 -C.sub.10 -alkinylene, a
substituted C.sub.4 -C.sub.10 -alkinylene, which is substituted
once or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1
-C.sub.6 -alkoxy, and C.sub.2 -C.sub.10 -alkylene, C.sub.2
-C.sub.10 -alkylene, C.sub.4 -C.sub.10 -alkenylene, or C.sub.4
-C.sub.10 -alkinylene, wherein one to three methylene units are
is6sterically replaced by O, S, NR.sup.10, CO, SO, or SO.sub.2,
wherein R.sup.10 has the same meaning as R.sup.9, but is selected
independently thereof; E is selected from the group consisting of
##STR307## wherein the heterocyclic ring may have a double bond and
n and p are, independent of each other, 0, 1, 2 or 3 where
n+p.ltoreq.4, wherein q is 1, 2 or 3; R.sup.11 is selected from the
group consisting of hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, and C.sub.2 -C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from the group consisting of hydrogen, C.sub.1
-C.sub.6 -alkyl and an oxo group adjacent to a nitrogen atom, or
R.sup.11 and R.sup.12, may together, form a C.sub.1 -C.sub.3
-alkylene bridge under formation of a bicyclic ring system; G is
selected from the group consisting of G.sup.1, G.sup.2, G.sup.3,
G.sup.4 and G.sup.5, wherein G.sup.1 is --(CH.sub.2).sub.r
--(CR.sup.14 R.sup.15).sub.s --R.sup.13 r is 0, 1, 2 or 3 and s is
0 or 1 R.sup.13 is selected from the group consisting of hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3
-C.sub.6 -alkinyl, C.sub.3 -C.sub.8 -cycloalkyl, saturated or
unsaturated, four to seven-membered heterocycles, which contain one
or two hetero-atoms selected from N, S and O, benzyl, phenyl,
monocyclic aromatic five and six-membered heterocycles, which
contain one to three hetero-atoms selected from N, S and O and are
either bound directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated carbocyclic ring
system with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage occurs either over an aromatic or a
hydrogenated ring and either directly or over a methylene group,
and anellated bi- and tricyclic aromatic or partially hydrogenated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms are selected from N,
S and O and the linkage occurs either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from the group
consisting of hydrogen, hydroxy, methyl, benzyl, phenyl, monocyclic
aromatic five and six-membered heterocycles, which contain one to
three hetero-atoms selected from N, S and O and are either bound
directly or over a methylene group, anellated bi- and tricyclic
aromatic or partially hydrogenated carbocyclic ring systems with 8
to 16 ring atoms and at least one aromatic ring, wherein the
linkage occurs either over an aromatic or a hydrogenated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic and partially hydrogenated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms are selected from N, S and O and
the linkage can occur either over an aromatic ring or a
hydrogenated ring and either directly or over a methylene group;
G.sup.2 is .dbd.(C).sub.u R.sup.13 R.sup.15 wherein, R.sup.13 and
R.sup.15 have the above meaning and u is 0 or 1, or u=1, and
R.sup.13 and R.sup.15 together with a carbon atom to which they are
attached form a ring system selected from the group consisting of
C.sub.2 -C.sub.8 -cycloalkyl, saturated, four to seven-membered
heterocycles which contain one or two hetero-atoms selected from N,
S and O; anellated bi- and tricyclic partially hydrogenated
carboxocyclic ring system with 8 to 16 ring atoms and at least one
aromatic ring; and anellated bi-and tricyclic partially
hydrogenated heterocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring, wherein one to three ring atoms are
selected from N, S and O; or, u=0, and R.sup.13 and R.sup.15
together with the carbon atom C.sub.E of ring E to which they are
attached form a ring system C.sub.E R.sup.13 R.sup.15 selected from
the group consisting of cycloalkyl, saturated, four to
seven-membered heterocycles which contain one or two hetero-atoms
selected from N, S and O; anellated bi- and tricyclic partially
hydrogenated carbocyclic ring systems with 8 to 16 ring atoms and
at least one aromatic ring; and anellated bi- and tricyclic
partially hydrogenated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein 1 to 3 ring atoms can
be selected from N, S and O; G.sup.3 is selected from ##STR308##
wherein r, s, and the substituents R.sup.13, R.sup.14, and R.sup.15
have the above meanings, or the group
and
Description
The invention relates to new piperidinyl-substituted
pyridyl-alkane, alkene and alkine carboxamides with a saturated or
one or several-fold unsaturated hydrocarbon residue in the
carboxylic acid portion, methods for the synthesis of these
compounds, medicaments containing these and their production as
well as their therapeutic use especially as cytostatic agents and
immunosuppresive agents, for example, in the treatment or
prevention of various types of tumors and control of immune
reactions, for example of autoimmune diseases.
A pressing need exists for new pharmaceuticals and/or medicaments
for cytostatic and immunosuppressive therapy which not only possess
a strong activity, but also exert diminished side effects in
comparison to many classical cancerostatic agents. At the same time
treatment of a broad as possible spectrum of tumors should be made
accessible. Furthermore, effective cytostatic agents for an
efficient therapy should be made available. Active ingredients of
this type should also be exceptionally suitable in the mentioned
indications for a combination therapy, be it in connection with
other cytostatic agents or with radiation (for example X-rays,
radioactive elements, such as cobalt, or linear accelerator, etc.),
with operative procedures, heat treatment, etc.
Additionally, from another point of view, there exists a strong
need in the field of tumor therapy for new compounds, for example
for overcoming or avoiding resistances, which enrich the pallet of
cancerostatics based on new modes of action in the ideal case.
This object was successfully solved by the creation of the
piperidinyl-substituted pyridylalkane, alkene and alkine
carboxamide derivatives as defined in detail in the claims and
medicaments containing these as well as the use of these compounds,
optionally in combination with other suitable active ingredients
and adjuvants, for cytostatic and immunosuppressive therapy or
prevention.
It is known that various pyridine compounds or substituted in a
specific manner have pharmacologically useful properties; however,
in contrast to the actions of the compounds according to the
invention, these lie in completely different fields of
indication.
Thus, .omega.-pyridyl-alkane and/or alkene amides with
anti-allergic activity are described in EP 0 210 782 which are
referred to as having a 5-lipoxygenase-inhibiting and
anti-histamine action, wherein the amide components of these
compounds contain a piperizine or homopiperizine ring and the
pyridine ring can be linked together in the 2-, 3- or 4-position.
JP 63,179,869 describes further pyridyl amides,
.omega.-pyridylalkane and alkene amides as anti-allergic effective
substances containing a substituted piperidine ring in the amine
component. However, corresponding overlapping compound groups are
excluded from the present claimed scope of protection according to
the invention. Similarly compounds with the same properties are
mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med.
Chem. 1989, 583-593 whereby corresponding known substitutions are
also excluded from the present scope of protection.
Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein
the amide portion is bound over an aryl-substituted alkyl chain
with a piperidine ring or piperidine ring or piperazine ring, are
described for example in EP-A-0 428 434 or in EP-A-0 512 902 as
antagonists of the neurokinin receptor and substance P.
Furthermore, pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides
and analogous ureas, wherein the pyridine ring is bound directly or
over a methylene bridge with the amide group are disclosed in
EP-A-0 479 601 as active ingredients with anti-arrhythmic
properties.
Other structurally closely related compounds are represented by the
piperidine compounds described in EP-A-0 330 026. These known
compounds are distinguished by an anti-cholinesterase activity, an
anti-amnesia activity as well as activities directed against
hyperkinesia, senile dementia, mania and Alzheimer's disease.
In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid
esters and amides as well as their use for the treatment of tumor
conditions is described. These compounds differ from the compounds
according to the invention described below in very important
structural features, for example by the dicarboxyl grouping on the
pyridine ring or the absence of the hydrocarbon chain between the
pyridine ring and the amide grouping. The compounds disclosed in WO
89/07 443 in the form of optically pure R(-)-niguldipin and further
analogous dihydropyridines with cytotoxic activity have larger
structural differences. However, as compared to these known
compounds, the compounds according to the invention possess a
higher activity and a wider spectrum of action despite the large
structural differences.
In the international PCT patent applications WO 96/31477 or for
example WO 96/31478 tricyclic anellated compounds are described
which possess an anti-proliferative activity. All of these
compounds described therein are distinguished in that they must
imperatively possess a tricyclic anellated ring system with at
least one nitrogen atom, for example 6,
11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinyl ring system as a
pharmaphoric group. The molecule portion at the other end of this
tricyclic anellated system is uncommonly variable such that the
pyridyl substitution given therein among numerous substitution
possibilities merely represents one of many variation
possibilities. A further meaningful difference in the substitution
of these molecules in comparison to the compounds according to the
invention is to be seen in the lack of the present structural
element D (i.e. the inserted, optionally unsaturated hydrocarbon
chain between the two essential terminal and/or opposite
heterocycles); expressed in other words, the known compounds have a
direct bond between the carboxy group and the piperidine ring.
A further essential difference of the compounds according to the
invention in comparison to these known tricyclic anellated
compounds is to be recognized in the presence of the terminal
3-pyridyl-substitution which must be present. The presence of this
heterocyclic ring required according to the invention as well as
this particular bond site in the substituted compounds according to
the invention in comparison to the above mentioned
anti-proliferative compounds of the state of the art with a
tricyclic ring system is to be understood as a meaningful
indication that, in a completely surprising manner, the pyridyl
group is responsible for the anti-tumor action according to the
invention.
In fact, the compounds according to the invention cover a different
tumor spectrum from those named in the PCT/WO publications with
this necessarily present tricyclic anellated ring system. In the
mentioned PCT/WO publications of the state of the art, a treatment
possibility in tumors is merely mentioned which is made in
connection with a potential inhibition of the farnesyl protein
transferase, whereby this mechanism relates to the expression of
the activated rasoncogene. In contrast to this, the presently
claimed new compounds with the 3-pyridyl-substitution required
according to the invention are not limited to the therapy of tumor
cells of this type with abnormal production of the ras-oncogene;
rather, the therapy possibilities with the new compounds according
to the invention extend to the combat of numerous other types of
tumors with different causal mechanisms as well as
immunosuppressive treatment possibilities such as autoimmune
diseases.
In view of this art, the finding demonstrated in the
pharmacological experimental section below according to which the
compounds according to the general formula (I) with the particular
substitutions defined below have superior pharmacological
activities which make them particularly suitable in an excellent
manner for the therapy of tumor illnesses over a broad
anti-proliferative spectrum, was completely unexpected. The
pharmacological finding that, aside from the cytostatic
effectiveness, and the ability to inhibit abnormal cell growth
especially with different tumor spectra, the compounds according to
the invention also possess immunosuppressive properties and
additionally favorable abortive properties without harmful
mutagenic effects is to be considered as equally surprising.
Pyridyl compounds wherein, a non-aromatic heterocyclic ring with
merely one ring nitrogen atom and optionally an additional ring
oxygen atom, preferably a piperidinyl residue, is also
incorporated--however, in opposite orientation--as well as their
use especially as cytostatic agents are subject matter of the older
patent application P 196 24 704.7-44 which has not yet been
published.
Therewith, the most important differentiating feature of the new
compounds according to the invention with respect to these older,
non-prepublished compounds is the orientation of the structural
feature E which in the present application is always integrated in
the opposite direction in the general formula (I). This novel
construction of these structurally complicated compounds not only
has an unexpected positive effect for the amenability of the
synthesis, but also for the multiple variation possibilities of the
structural element G found at the outer end of the molecule. As a
result of this particular molecular structure now found, a novel
class of compounds with, among others, pronounced cancerostatic
effect is offered.
These new piperidinyl-substituted pyridyl carboxamides correspond
to the following general formula: ##STR2##
wherein the structural element E has the following meaning:
##STR3##
and whereby the heterocyclic ring can optionally have a double bond
and n and p can be, independent from each other, 0, 1, 2 or 3 with
the proviso that n+p.ltoreq.4, and whereby q is 1; 2 or 3.
The substituent E can especially be present in the form of
azetidine, pyrrolidine, piperidine, hexahydroazepine,
octahydroazocine, morpholine, hexahydro-1,4-oxazepine and
octahydro-1,4-oxacocine.
The meaning of the remaining substituents and the preferred
embodiments of the compound groups according to the invention
falling under the general formula as well as particularly preferred
end products are defined in claims 1 to 7 in detail. In this
connection, reference is also made to the substituent meanings
which are illustrated as follows and are partially emphasized as
preferred.
The compounds of Formula (I), which represent the end products can
optionally exist as cis- and trans-isomers, E- and Z-isomers, for
example when A is a cyclopropane ring or D contains one or more
double bonds. Subject matter of the invention is the pure isomers
as well as their mixtures.
Furthermore, the compounds of Formula (I) can contain one or more
asymmetric carbon atoms and, as a result, exist in the form of
different optical isomers (enantiomers, diastereomers). The
invention includes all optical isomers and their racemic or
non-racemic mixtures. Finally, compounds of Formula (I) can exist
as endo/exo-isomers in case the ring system E is bicyclic. The pure
endo- and exo-isomers as well as their mixtures are also comprised
by the invention.
Compounds of Formula (I), in which G is a heterocyclic aromatic
ring or contains such in an anellated ring system can optionally be
present as tautomers when this heterocyclic ring is substituted by
free hydroxy-, mercapto- or amino groups. In this case, the
invention includes all tautomeric forms.
Subject matter of the invention are further pharmacologically
acceptable acid addition salts of the compounds of Formula (I) with
inorganic or organic acids. Preferable examples for addition salts
with suitable inorganic acids are hydrochlorides, hydrobromides,
hydroiodides, sulfates and phosphates. Addition salts of organic
acids are preferably acetates, benzoates, citrates, fumarates,
gluconates, malates, maleates, methanesulfonates, lactates,
oxalates, succinates, tartrates and tosylates.
Compounds of Formula (I) as well as their acid addition salts can
also be optionally present as hydrates or other solvates. The
invention includes such hydrates and solvates.
In the compounds of Formula (I), the definitions for the atoms or
atomic groups preferably have the following meanings: Halogen means
fluorine, chlorine, bromine or iodine;
Alkyl can be straight chained or branched and preferably signifies
a C.sub.1 -C.sub.6 -alkyl residue, especially a methyl-, ethyl-,
propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-,
cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-,
cyclopropylethyl-, cyclobutylmethyl- or hexyl group.
Alkylene signifies for example methylene, ethylene, propylene,
tetramethylene, pentamethylene, hexamethylene, heptamethylene,
octamethylene, nonamethylene or decamethylene.
Alkenyl preferably signifies C.sub.3 -C.sub.6 -alkenyl and can be
straight chained or branched and preferably signifies an allyl-,
2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-,
4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-,
5-hexenyl-, 4-methyl-3-pentenyl- or
2,2-dimethyl-3-butenyl-group.
Alkenylene signifies for example ethenylene, propenylene,
butenylene, pentenylene, hexenylene, hexadienylene, heptenylene,
octenylene, nonenylene or decenylene.
Alkinyl preferably signifies C.sub.2 -C.sub.6 -alkinyl which can be
straight chained or branched and can preferably signify an
ethinyl-, propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-,
5-hexinyl- or 4-methyl-2-pentinyl group.
Alkinylene signifies for example propinylene, butinylene,
pentinylene, hexinylene, hexeninylene, heptinylene, octinylene,
noninylene or decinylene.
Cycloalkyl is preferably a C.sub.3 -C.sub.8 -cycloalkyl residue,
especially a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-,
cycloheptyl- or cyclooctyl group.
Hydroxyalkyl contains a hydroxyl group in one of the above
mentioned alkyl residues, especially in a C.sub.1 -C.sub.6 -alkyl
residue, whereby among the C.sub.1 -C.sub.6 -hydroxyalkyl residues,
the hydroxymethyl- and the hydroxyethyl residue are preferred.
Aside from the oxygen atom, alkoxy, preferably C.sub.1 -C.sub.6
alkoxy, alkenyloxy, and alkinyloxy especially C.sub.1 -C.sub.6
contain one of the above mentioned preferred C.sub.1 -C.sub.6
-alkyl-, C.sub.3 -C.sub.6 -alkenyl- and/or C.sub.3 -C.sub.6
-Alkinyl groups. Particularly preferred groups for this are the
methoxy-, ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and
propargyloxy groups.
Alkoxy, especially C.sub.1 -C.sub.6 -alkoxy, entirely or partially
replaced by fluorine is for example difluoromethoxy,
trifluoromethoxy or 2,2,2-trifluoroethoxy.
Aside from the sulphur atom, alkylthio, alkenylthio, alkinyl-thio
contain one of the above mentioned preferred C.sub.1 -C.sub.6
-alkyl-, C.sub.3 -C.sub.6 -alkenyl- or C.sub.3 -C.sub.6 -alkinyl
groups. Preferred groups among these are the methylthio-,
ethylthio-, isopropylthio- and tert-butylthio groups.
Cyclopentyloxy- and cyclopentylthio- and/or cyclohexyloxy- and
cyclohexylthio residues represent preferred C.sub.3 -C.sub.8
-cycloalkyloxy and C.sub.3 -C.sub.8 -cycloalkylthio.
Aside from the oxygen atom, alkanoyloxy groups preferably contain
an aliphatic acyl group with 1 to 7 carbon atoms. Among preferred
alkanoyloxy groups are the acetoxy-, propionyloxy- and pivaloyloxy
groups.
Alkoxycarbonyl groups, preferably C.sub.2 -C.sub.7 -alkoxycarbonyl
groups contain, aside from the carbonyl group, one of the above
mentioned alkoxy groups, especially C.sub.1 -C.sub.6 -alkoxy
groups. Preferred alkoxycarbonyl groups are the methoxycarbonyl-,
ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl- and
tert-butoxycarbonyl groups.
Aside from the oxygen atom, alkoxycarbonyloxy groups preferably
contain one of the above mentioned C.sub.2 -C.sub.7
-alkoxy-carbonyl residues. Among preferred alkoxycarbonyl groups
are the methoxycarbonyloxy-, ethoxycarbonyloxy-,
isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and
tert-butoxycarbonyl groups as well as allyloxycarbonyloxy
groups.
Aside from the carbonyl group, alkylaminocarbonyl, especially
C.sub.2 -C.sub.7 -alkylaminocarbonyl and dialkylaminocarbonyl
groups, preferably C.sub.3 -C.sub.13 -dialkylaminocarbonyl groups,
contain an alkylamino- and/or dialkylamino residue whose alkyl
groups correspond especially to the C.sub.1 -C.sub.6 -alkyl groups
of the above description. Preferred groups are the
dimethylaminocarbonyl-, diethylaminocarbonyl- and
diisopropylamino-carbonyl groups.
Aside from the unsubstituted amino group, the amino groups of the
Formula NR.sup.5 R.sup.6 are one of the below mentioned alkylamino
groups, especially C.sub.1 -C.sub.6 -alkylamino groups and/or
dialkyl-amino groups, especially di-(C.sub.1 -C.sub.6 -alkyl)amino
groups.
Alkylamino especially contains one of the above mentioned C.sub.1
-C.sub.6 -alkyl groups. Preferred groups are the methylamino-,
ethylamino-, propylamino-, isopropylamino-, butylamino-, and the
tert-butylamino groups.
The preferred di-(C.sub.1 -C.sub.6 -alkyl)amino residue carries two
of the same or different of the above mentioned C.sub.1 -C.sub.6
-alkyl groups on the nitrogen atom. Preferred groups are the
dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-,
isopropyl-, methylamino-, dibutylamino- or tert-butylmethylamino
groups.
Acyl, especially C.sub.1 -C.sub.6 -acyl, signifies the residue of
an aliphatic saturated or unsaturated, straight chained, branched
or cyclic carboxylic acid. Preferred acyl residues are formyl-,
acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-,
methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-,
cyclobutylcarbonyl-, hexanoyl- and dimethylacryloyl groups.
Alkanesulfonyl, especially C.sub.1 -C.sub.6 -alkanesulfonyl is
preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-,
butanesulfonyl-, pentanesulfonyl- or hexanesulfonyl groups.
Saturated or unsaturated, preferably four- to eight-membered
heterocycles with one or two hetero-atoms, are for example
azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,
tetrahydropyran, tetrahydropyridine, piperidine, tetrahydroazepine,
hexahydroazepine, octahydroazocine, pyrazolidine, piperazine,
morpholine, thiomorpholine, thiomorpholin-1,1-dioxide,
hexahydrodiazepine or hexahydrooxazepine.
Preferred monocyclic aromatic five- or six-membered heterocycles
with one to three hetero-atoms are for example furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl.
Anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring are preferably benzocyclobutyl, indanyl, indenyl,
naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl,
fluoroenyl, anthryl, dihydroanthryl, phenanthryl,
dihydrophenanthryl, dihydrodibenzocycloheptenyl,
tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or
tetrahydrodibenzocyclooctenyl. Their mono- or dioxo-derivates, i.e.
for example the following rings: indanone, tetralone, anthrone,
anthraquinone, fluoroenone, phenanthrone, dibenzocycloheptenone,
dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are
also to be understood as partially hydrated carbocyclic ring
systems.
Anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring are, for example, imidazothiazolyl, benzofuryl,
dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl,
indolinyl, isoindolinyl, bennzimidazolyl, indazolyl, benzoxazolyl,
benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl,
benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl,
isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl,
thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl,
dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl,
quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,
pyridoindolyl, acridinyl, phenanthridinyl, dihydrophenanthridinyl,
dibenzoisoquinolinyl, dihydrodibenzoisoquinolinyl, phenothiazinyl,
dihydrodibenzooxepinyl, benzocycloheptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
octahydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepnyl,
octahydrodibenzoazepinyl, benzocycloheptapyridyl,
dihydrobenzocycloheptapyridyl, pyridobenzoazepinyl,
dihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl,
dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,
dihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl or
dihydropyridobenzothiazepinyl.
Furthermore, their mono- or dioxo-derivates and/or optionally their
possible tautomers are also to be understood as partially hydrated
heterocyclic ring systems, i.e. for example the residues of
indolinone, isatin of benzoxazolone and/or its tautomer
hydroxybenzoxazole, of benzisoxazolone, benzothiazolone,
benzoisothiazolone and benzimidazolone and/or their corresponding
tautomers hydroxybenzisoxazole, hydroxybenzothiazole,
hydroxybenzoisothiazole and hydroxybenzimidazole, as well as
indazolinone, of oxazolopyridinones, thiazolopyridinones,
pyrazolopyridinones and imidazopyridinones and/or their
corresponding tautomers hydroxyoxazolopyridine,
hydroxythiazolopyridine, hydroxypyrazolopyridine and
hydroxyimidazopyridine, the residues for the series chromanone,
chromone, quinolinone, dihydroquinolinone, tetrahydrocarbazolone,
acridone, phenannthridone, benzoisoquinolone,
dihydrodibenzooxepinones, benzocycloheptathiophenones,
dihydrothienobenzothiepinones, dihydrodibenzothiepinones,
dihydrodibenzoazepinones, benzocycloheptapyridinones,
dihydropyridobenzoazepinones,
dihydropyridobenzodiazepinones/dihydropyridobenzoxazeninones,
dihydrodibenzothiazepinones and of
dihydropyridobenzothiazepinones.
Saturated and unsaturated monocyclic, four- to eight-membered
heterocycles (as the group --NR.sup.13 R.sup.15) which, aside from
the essential nitrogen atom, can optionally contain one or two
further hetero-atoms selected from N and/or S and/or O, are for
example azetidine, pyrrolidine, piperidine,
(1H)-tetrahydropyridine, hexahydroazepine, (1H)-tetrahydroazepine,.
octahydroazocine. pyrazolidine, piperazine, hexahydrodiazepine,
morpholine, hexahydroxazepine, thiomorpholine or
thiomorpholin-1,1-dioxide.
Saturated or unsaturated bi- or tricyclic, anellated or bridged
heterocycles with 8 to 16 ring atoms, (in the form of the group
--NR.sup.13 R.sup.15) which, aside from the essential nitrogen
atom, can optionally contain one or two further hetero-atoms,
selected from N and/or S and/or O, are for example
5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane,
7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane,
2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane,
2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane,
indoline, isoindoline, (1H)-dihydroquinoline,
(1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline,
(1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine,
(4H)-dihydrobenothiazine, (1H)-tetrahydrobenzo[b]azepine,
(1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine,
(5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine,
(10H)-dihydrophenanthridine, 1,2,3,4-tetrahydroacridanone,
(10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine,
(5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine,
dihydrobenzo[d,e]isoquinoline, (5H)-dihydrodibenzodiazepine,
(5H)-benzo[b]pyrido[f]azepine,
(5H)-dihydrobenzo[b]pyrido-[f]azepine
(11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine, (5H)-tetrahydrodibenzazocine,
(11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one,
(11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one.
Spirocyclic ring system (in the form of the group ER.sup.13,
R.sup.15), comprising the residue E and a C.sub.3 -C.sub.8
-cycloalkane ring, are for example 2-azaspiro[3,4]octane, or the
residue 2-azaspirononanes, azaspirodecanes and
azaspiroundecanes.
Spirocyclic ring systems (in the form of the group ER.sup.13,
R.sup.15), comprising the residue E and a saturated four to
seven-membered heterocycle with one or two hetero-atoms
respectively are for example 5,8-dioxa-2-aza-spiro[3,4]octane or a
residue from the series of dioxaazaspirononanes,
dithiaazaspirononanes, oxadiazaspirononanes, triazaspirononanes,
diazaspirodecanes, dioxaazaspirodecanes, dithiaazaspirodecanes,
oxadiazaspirodecanes, triazaspirodecanes, dioxaazaspiroundecanes,
dithiaazaspiroundecanes, oxadiazaspiroundecanes or
triazaspiroundecanes as well as their mono- and dioxo
derivates.
Spirocyclic ring systems (in the form of the group ER.sup.13
R.sup.15), comprising the residue E and an anellated, bi- or
tricyclic, partially hydrated carbocyclic or heterocyclic ring
system are preferably spiro[indan-piperidines],
spiro[piperidin-tetrahydronaphthalines],
spiro[benzodioxol-pyrrolidines], spiro[benzodioxol-piperidines],
spiro[benzodioxol-hexahydroazepines],
spiro[benzo-1,3-dioxin-piperidines],
spiro[dihydrobenzo-1,3-oxazin-piperidines],
spiro[oxodihydrobenz-1,3-oxazin-piperidines] and
spiro[piperidin-oxo-1,2,3,4-tetrahydrochinazolines].
Very particularly preferred embodiments of the invention are
represented by the following end products:
N-[4-(4-phenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide;
N-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-3-pyr
idin-3-yl-acrylamide;
N-[4-(4-benzotriazol-1-yl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(hydroxy-diphenylmethyl)-piperidin-1-yl]-butyl}-2-(pyridin-3-yloxy)
-acetamide;
N-[4-(4,4-diphenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}
-3-pyridin-3-yl-propionamide dihydrochloride/semi-isopropanol;
N-{4-[4-(6,11-dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}
-5-pyridin-3-yl-pentanamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl
]-butyl}-3-pyridin-3-yl-propionamide;
N-{4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl
]-butyl}-3-pyridin-3-yl-acrylamide;
N-[4-(4-diphenylphosphinoyloxy-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acryla
mide;
N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-3-pyridin-3-yl-acrylamide.
Concretely, the invention relates to new compounds of the general
Formula (I) ##STR4##
wherein R.sup.1 is selected from hydrogen, hydroxy, halogen, cyano,
carboxy; saturated, single or several-fold unsaturated, branched or
straight chained or cyclic hydrocarbon residues such as alkyl,
alkenyl, alkinyl or cycloalkyl; trifluoromethyl or hydroxyalkyl;
aryl such as phenyl or heteroaryl such as pyridyl; alkoxy,
cycloalkyloxy, alkenyloxy, alkinyloxy or aralkyloxy such as the
benzyloxy group, alkoxycarbonyl; aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkanoyloxy, alkoxycarbonyloxy; alkylthio,
cycloalkylthio, alkenylthio, alkinylthio; aryloxy such as phenoxy,
heteroaryloxy such as pyridyloxy, heteroarylthio such as
pyridylthio, and NR.sup.5 R.sup.6, whereby R.sup.5 and R.sup.6 are
selected independent of each other from hydrogen, saturated or
unsaturated hydrocarbon residues such as alkyl, alkenyl, alkinyl,
or aryl such as phenyl and aralkyl such as benzyl; R.sup.2 is
selected from hydrogen, halogen, cyano, saturated hydrocarbon
residues such as alkyl, or halogenated hydrocarbon residues such as
trifluoromethyl, hydroxy, alkoxy, aralkyloxy residues such as
benzyloxy, as well as alkanoyloxy, whereby R.sup.1 and R.sup.2, in
the case that they are immediately adjacent to each other,
optionally form a bridge which is selected from --(CH.sub.2).sub.4
-- and --(CH.dbd.CH).sub.2 -- and --CH.sub.2 O --CR.sup.7 R.sup.8
--C--, wherein R.sup.7 and R.sup.8 are selected independently of
each other from hydrogen and alkyl residues; R.sup.3 is selected
from hydrogen, halogen, saturated hydrocarbon residues such as
alkyl, or halogenated hydrocarbon residues such as trifluoromethyl,
or hydroxyalkyl; R.sup.4 is selected from hydrogen, hydroxy,
saturated, single or several-fold unsaturated, branched or straight
chained or cyclic hydrocarbon residues such as alkyl, alkenyl,
alkinyl or cycloalkyl, alkoxy and aralkyloxy such as benzyloxy; k
is 0 or 1; A is selected from alkylene with at least 2 carbon atoms
which is optionally substituted one to three-fold by straight
chained or branched chained hydrocarbon residues such as alkyl,
hydroxy, alkoxy, halogen such as fluorine, or aryl such as phenyl,
alkylene with at least 2 carbon atoms, wherein a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2
whereby, with the exception of CO, the isosteric substitution
cannot be adjacent to the amide group and, in NR.sup.9, the residue
R.sup.9 is selected from hydrogen, alkyl, alkenyl, alkinyl, acyl or
alkanesulfonyl; cycloalkylene such as 1,2-cyclopropylene;
alkenylene with at least 2 carbon atoms which is optionally
substituted one to three-fold by alkyl, hydroxy, alkoxy, fluorine,
cyano or aryl such as phenyl; kadienylene with at least 4 carbon
atoms, which is optionally substituted once or twice by alkyl,
fluorine, cyano or aryl such as phenyl; 1,3,5-hexatrienylene, which
is optionally substituted by alkyl, fluorine, cyano or aryl such as
phenyl; as well as ethinylene; D is selected from alkylene with at
least 2 carbon atoms, which is optionally substituted once or twice
by alkyl, hydroxy, or alkoxy; alkenylene with at least 4 carbon
atoms, which is optionally substituted once or twice by alkyl,
hydroxy, or alkoxy; alkinylene with at least 4 carbon atoms, which
is optionally substituted once or twice by alkyl, hydroxy, or
alkoxy; as well as alkylene, alkenylene or alkinylene with at least
2 or 4 carbon atoms respectively, wherein one to three methylene
units is each isosterically replaced by O, S, NR.sup.10, CO, SO or
SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9 but is
selected independently thereof; E is selected from ##STR5## whereby
the heterocyclic ring can optionally have a double bond and n and p
can be, independent of each other, 0, 1, 2 or 3 with the proviso
that n+p.ltoreq.4. q is 1, 2 or 3; R.sup.11 is selected from
hydrogen, alkyl, hydroxy, hydroxymethyl, carboxy, or alkoxycarbonyl
with at least 2carbon atoms and R.sup.12 is selected from hydrogen,
alkyl or an oxo group adjacent to a nitrogen atom or R.sup.11 and
R.sup.12, optionally together, form a C.sub.1 -C.sub.3 -alkylene
bridge under formation of a bicyclic ring system; G is selected
from G1, G2, G3, G4 or G5, wherein G1 is the residue
According to a further embodiment of the invention, the new,
pyridylalkane, pyridylalkene and pyridylalkine acid amide compounds
correspond with respect to their substitutions formula (I)
##STR9##
wherein R.sup.1 is selected from hydrogen, halogen, cyano, C.sub.1
-C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6
-alkinyl, trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, C.sub.1
-C.sub.6 -hydroxyalkyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, C.sub.3
-C.sub.6 -alkenyloxy, C.sub.3 -C.sub.6 -alkinyloxy, benzyloxy,
C.sub.1 -C.sub.7 -alkanoyloxy, C.sub.2 -C.sub.7 -alkoxycarbonyloxy,
C.sub.1 -C.sub.6 -alkylthio, C.sub.3 -C.sub.6 -alkenylthio, C.sub.3
-C.sub.6 -alkinylthio, C.sub.3 -C.sub.8 -cycloalkyloxy, C.sub.3
-C.sub.8 -cycloalkylthio, C.sub.2 -C.sub.7 -alkoxycarbonyl,
aminocarbonyl, C.sub.2 -C.sub.7 -alkylaminocarbonyl, C.sub.3
-C.sub.13 -dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
phenylthio, pyridyloxy, pyridylthio, and NR.sup.5 R.sup.6, wherein
R.sup.5 and R.sup.6 are selected independently of each other from
hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl,
C.sub.3 -C.sub.6 -alkinyl, benzyl and phenyl; R.sup.2 is selected
from hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl, hydroxy, C.sub.1 -C.sub.6 -alkoxy, benzyloxy and
C.sub.1 -C.sub.7 -alkanoyloxy; R.sup.1 and R.sup.2, if adjacent,
optionally form a bridge selected from --(CH.sub.2).sub.4 -- and
--(CH.dbd.CH).sub.2 -- or --CH.sub.2 O--CR.sup.7 R.sup.8 --O--,
wherein R.sup.7 and R.sup.8 are selected independently from each
other from hydrogen and C.sub.1 -C.sub.6 -alkyl; R.sup.3 is
selected from hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl and C.sub.1 -C.sub.6 -hydroxyalkyl; R.sup.4 is
selected from hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6
-alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.3 -C.sub.6 -cycloalkyl,
hydroxy, C.sub.1 -C.sub.6 -alkoxy and benzyloxy; k is 0 or 1, A is
selected from C.sub.1 -C.sub.6 -alkylene, optionally substituted
one to three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy, C.sub.1
-C.sub.3 -alkoxy, fluorine, or phenyl, C.sub.2 -C.sub.6 -alkylene,
in which a methylene unit is isosterically replaced by O, S,
NR.sup.9, CO, SO or SO.sub.2, whereby, with the exception of CO,
the isosteric substitution cannot be adjacent to the amide group
and R.sup.9 is selected from hydrogen, C.sub.1 -C.sub.6 -alkyl,
C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl, C.sub.1
-C.sub.6 -acyl or C.sub.1 -C.sub.6 -alkanesulfonyl,
1,2-cyclopropylene, C.sub.2 -C.sub.6 -Alkenylene, optionally
substituted once to three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy,
C.sub.1 -C.sub.3 -alkoxy, fluorine, cyano or phenyl, C.sub.4
-C.sub.6 -alkadienylene, optionally substituted once or twice by
C.sub.1 -C.sub.3 -alkyl, fluorine, cyano or phenyl;
1,3,5-hexatrienylene, optionally substituted by C.sub.1 -C.sub.3
-alkyl, fluorine, cyano or phenyl, and ethinylene D is selected
from C.sub.2 -C.sub.10 -alkylene, optionally substituted once or
twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy; C.sub.4 -C.sub.10 -alkenylene, optionally substituted once
or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy; C.sub.4 -C.sub.10 -alkinylene, optionally substituted once
or twice by C.sub.1 -C.sub.6 -alkyl, hydroxy, or C.sub.1 -C.sub.6
-alkoxy; and C.sub.2 -C.sub.10 -alkylene, C.sub.4 -C.sub.10
-alkenylene or C.sub.4 -C.sub.10 -alkinylene, in which one to three
methylene units are isosterically replaced by O, S, NR.sup.10, CO,
SO or SO.sub.2, whereby R.sup.10 has the same meaning as R.sup.9,
but is selected independently thereof; E is selected from ##STR10##
whereby the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3 with the
proviso that n+p.ltoreq.4, wherein q is 1,2 or 3; R.sup.11 is
selected from hydrogen, C.sub.1 -C.sub.6 -alkyl, hydroxy,
hydroxymethyl, carboxy, or C.sub.2 C.sub.7 -alkoxycarbonyl and
R.sup.12 is selected from hydrogen, C.sub.1 -C.sub.6 -alkyl or an
oxo group adjacent to a nitrogen atom, R.sup.11 and R.sup.12
optionally together, form a C.sub.1 -C.sub.3 -alkylene bridge under
formation of a bicyclic ring system; G is selected from G1, G2, G3,
G4 or G5, whereby G.sup.1 is --(CH.sub.2).sub.r --(CR.sup.14
R.sup.15).sub.s --R.sup.13 (G1) r is a number from 0 to 3, s is 0
or 1 and R.sup.13 is selected from hydrogen, C.sub.1 -C.sub.6
-alkyl, C.sub.3 -C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -alkinyl,
C.sub.3 -C.sub.8 -cycloalkyl; saturated or unsaturated, four to
seven-membered heterocycles, which can contain one or two
hetero-atoms selected from N and/or S and/or O; benzyl, phenyl;
monocyclic aromatic five or six-membered heterocycles, which can
contain one to three hetero-atoms selected from N and/or S and/or O
and are either bound directly or over a methylene group, anellated
bi- and tricyclic aromatic or partially hydrated carbocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein the linkage can occur either over an aromatic or a hydrated
ring and either directly or over a methylene group, anellated bi-
and tricyclic aromatic or partially hydrated heterocyclic ring
systems with 8 to 16 ring atoms and at least one aromatic ring,
wherein one to three ring atoms can be selected from N and/or S
and/or O and the linkage can occur either over an aromatic ring or
a hydrated ring and either directly or over a methylene group,
R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof; R.sup.15 is selected from hydrogen, hydroxy,
methyl, benzyl, phenyl; monocyclic aromatic five or six-membered
heterocycles, which can contain one to three hetero-atoms selected
from N and/or S and/or O and are either bound directly or over a
methylene group, anellated bi- and tricyclic aromatic or partially
hydrated carbocyclic ring systems with 8 to 16 ring atoms and at
least one aromatic ring wherein the linkage can occur either over
an aromatic or a hydrated ring and either directly or over a
methylene group, anellated bi- and tricyclic aromatic or partially
hydrated heterocyclic ring systems with 8 to 16 ring atoms and at
least one aromatic ring, wherein one to three ring atoms can be
selected from N and/or S and/or O and the linkage can occur either
over an aromatic ring or a hydrated ring and either directly or
over a methylene group, G.sup.2 is
According to a preferred embodiment, the invention relates to
compounds of the general Formula (I), ##STR14##
wherein R.sup.1 is selected from hydrogen, halogen, cyano, C.sub.1
-C.sub.6 -alkyl, trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl,
C.sub.1 -C-hydroxyalkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy,
benzyloxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.5
-alkanoyloxy, C.sub.1 -C.sub.4 -alkylthio, C.sub.2 -C.sub.5
-alkoxycarbonyl, aminocarbonyl, C.sub.2 -C.sub.5
-alkylaminocarbonyl, C.sub.3 -C.sub.9 -dialkylaminocarbonyl,
carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, and NR.sup.5
R.sup.6, whereby R.sup.5 and R.sup.6 are selected independently
from each other from hydrogen and C.sub.1 -C.sub.6 -alkyl; R.sup.2
is selected from hydrogen, halogen, cyano, C.sub.1 -C.sub.6 -alkyl,
trifluoromethyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy; R.sup.3 is
selected from hydrogen, halogen and C.sub.1 -C.sub.6 -alkyl;
R.sup.4 is selected from hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3
-C.sub.6 -alkenyl, C.sub.3 -C.sub.6 -cycloalkyl, hydroxy, C.sub.1
-C.sub.6 -alkoxy and benzyloxy; k is 0 or 1, A is selected from
C.sub.2 -C.sub.6 -alkylene, optionally substituted one to
three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy, fluorine, or
phenyl, C.sub.2 -C.sub.6 -alkylene, in which a methylene unit is
isosterically replaced by O, S, NR.sup.9, CO or SO.sub.2, whereby,
with the exception of CO, the isosteric substitution cannot be
adjacent to the amide group and R.sup.9 is selected from hydrogen,
C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -acyl or methanesulfonyl;
1,2-cyclopropylene, C.sub.2 -C.sub.6 -Alkenylene, optionally
substituted once to three-fold by C.sub.1 -C.sub.3 -alkyl, hydroxy,
fluorine, cyano or phenyl, C.sub.4 -C.sub.6 -alkadienylene,
optionally substituted once to twice by C.sub.1 -C.sub.3 -alkyl,
fluorine, cyano or phenyl; 1,3,5-hexatrienylene, optionally
substituted by C.sub.1 -C.sub.3 -alkyl, fluorine, cyano, and
ethinylene D is selected from C.sub.2 -C.sub.10 -alkylene,
optionally substituted once or twice by C.sub.1 -C.sub.3 -alkyl or
hydroxy; C.sub.4 -C.sub.10 -alkenylene, optionally substituted once
or twice by C.sub.1 -C.sub.3 -alkyl or hydroxy; C.sub.4 -C.sub.10
-alkinylene, optionally substituted once or twice by C.sub.1
-C.sub.3 -alkyl or hydroxy; as well as C.sub.2 -C.sub.10 -alkylene,
C.sub.4 -C.sub.10 -alkenylene or C.sub.4 -C.sub.10 -alkinylene, in
which one to three methylene units are isosterically replaced by O,
S, NR.sup.10, CO, SO or SO.sub.2, whereby R.sup.10 has the same
meaning as R.sup.9, but is selected independently thereof;
E is selected from ##STR15## whereby the heterocyclic ring can
optionally have a double bond and n and p can be, independent of
each other, 0, 1, 2 or 3 with the proviso that n+p.ltoreq.4, and q
is one or 2; R.sup.11 is selected from hydrogen, C.sub.1 -C.sub.3
-alkyl, hydroxy, hydroxymethyl, carboxy, or C.sub.2 -C.sub.7
-alkoxycarbonyl and R.sup.12 is selected from hydrogen or an oxo
group adjacent to a nitrogen atom or R.sup.1 l and R.sup.12,
optionally together, form a C.sub.1 -C.sub.3 -alkylene bridge under
formation of a bicyclic ring system; G is selected from G1, G2, G3,
G4 or G5, whereby G.sup.1 is
G.sup.2 is
According to a particularly preferred embodiment, the invention
relates to compounds of the general Formula (1) ##STR19##
wherein the substituents have the following meanings: R.sup.1 is
selected from hydrogen, halogen, cyano, methyl, ethyl,
trifluoromethyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, benzyloxy,
C.sub.1 -C.sub.5 -alkanoyloxy, methylthio, ethylthio,
methoxycarbonyl, tert-butoxycarbonyl aminocarbonyl, carboxy,
phenoxy, and phenylthio; R.sup.2 is selected from hydrogen,
halogen, trifluoromethyl, hydroxy; R.sup.3 is selected from
hydrogen, halogen; R.sup.4 is selected from hydrogen, C.sub.1
-C.sub.3 -alkyl, allyl, hydroxy and C.sub.1 -C.sub.3 -alkoxy; k is
0 or 1, A is selected from C.sub.2 -C.sub.6 -alkylene, optionally
substituted once or twice by C.sub.1 -C.sub.3 -alkyl, hydroxy or
fluorine; C.sub.2 -C.sub.6 -alkylene, in which a methylene unit is
isosterically replaced by O, S. CO, or SO.sub.2, whereby, with the
exception of CO, the isosteric substitution cannot be adjacent to
the amide group, C.sub.2 -C.sub.6 -alkenylene, optionally
substituted once or twice by C.sub.1 -C.sub.3 alkyl, hydroxy and/or
fluorine; C.sub.4 -C.sub.6 -alkadienylene, optionally substituted
by C.sub.1 -C.sub.3 -alkyl or one or two fluorine atoms;
1,3,5-hexatrienylene, optionally substituted by fluorine; D is
selected from C.sub.2 -C.sub.8 -alkylene, optionally substituted
once or twice by methyl or hydroxy; C.sub.4 -C.sub.8 -alkenylene,
optionally substituted once or twice by methyl or hydroxy; C.sub.4
-C.sub.8 -alkinylene, optionally substituted once or twice by
methyl or hydroxy; and C.sub.2 -C.sub.8 -alkylene, C.sub.4 -C.sub.8
-alkenylene or C.sub.4 -C.sub.8 -alkinylene, in which one to three
methylene units are isosterically replaced by O, S, NH, N(CH.sub.3)
N(COCH.sub.3), N(SO.sub.2 CH.sub.3), CO, SO or SO.sub.2 ; E is
selected from ##STR20## whereby the heterocyclic ring can
optionally have a double bond and n and p can be, independent of
each other, the number 0, 1, 2 or 3 with the proviso that
n+p.ltoreq.3 and q is 1 or 2; R.sup.11 is selected from hydrogen,
C.sub.1 -C.sub.3 -alkyl, hydroxymethyl, or carboxy, and R.sup.12 is
selected from hydrogen or an oxo group adjacent to a nitrogen atom
G is selected from G1, G2, G3, G4 or G5, whereby G.sup.1 is
The invention especially relates to compounds of the general
formula (I), ##STR24## according to claim 1, 2, 3 or 4, wherein the
substituents have the following meanings: R.sup.1 is selected from
hydrogen, fluorine, chlorine, bromine, methyl, ethyl,
trifluoromethyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, methylthio,
ethlythio, carboxy and phenoxy; R.sup.2 is selected from hydrogen,
chlorine and methyl; R.sup.3 is hydrogen; R.sup.4 is selected from
hydrogen, C.sub.1 -C.sub.3 -alkyl and hydroxy, k is 0 A is selected
from C.sub.2 -C.sub.6 -alkylene, which is optionally substituted
once or twice by hydroxy or fluorine; C.sub.2 -C.sub.6 -alkylene,
wherein a methylene unit is isosterically replaced by O, S or CO,
whereby, with the exception of CO, the isosteric substitution
cannot be adjacent to the amide group; C.sub.2 -C.sub.6 -alkenylene
which is optionally substituted by C.sub.1 -C.sub.3 -alkyl and/or
fluorine; C.sub.4 -C.sub.6 -alkadienylene; D is selected from
C.sub.4 -C.sub.8 -alkylene which is optionally substituted by
methyl or hydroxy; C.sub.4 -C.sub.8 -alkenylene, which is
optionally substituted by hydroxy; C.sub.4 -C.sub.8 -alkinylene,
which is optionally substituted by hydroxy; C.sub.4 -C.sub.8
-alkylene, C.sub.4 -C.sub.8 -alkenylene, C.sub.4 -C.sub.8
-alkinylene wherein a methylene unit is respectively isosterically
replaced by O, NH, N(CH.sub.3), CO or SO.sub.2 or an ethylene group
is isosterically replaced by a group NH--CO and/or CO--NH or a
propylene group is isosterically replaced by a group NH--CO--O
and/or O--CO--NH; E is selected from pyrrolidine, piperidine,
hexahydroazepine or morpholine, wherein the ring can be optionally
substituted by a methyene group and/or by an oxo group adjacent to
a nitrogen atom; G is selected from methoxycarbonylamino,
ethoxycarbonylamino tert-butoxycarbonylamino,
benzyloxycarbonylamino, trifluoroacetylamino,
diphenylphosphinoylamino, diphenylphosphinoyloxy,
diphenylmethyloxy, or a group ##STR25## whereby r is 0 or 1, and s
is 0 or 1, as well as u is 0 or 1, R.sup.13 is selected from
hydrogen, methyl, benzyl, phenyl; indanyl, indenyl, oxoindanyl,
naphthyl, tetrahydronaphthyl, fluorenyl, anthryl, phenanthryl,
dibenzocycloheptenyl, dihydrodibenzocycloheptenyl or
oxodihydrodibenzocycloheptenyl; thienyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl,
pyridazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl,
indolinyl, isoindolinyl, oxoindolinyl, dioxoindolinyl,
benzooxazolyl, oxobenzooxazolinyl, benzoisoxazolyl,
oxobenzoisoxazolinyl, benzothiazolyl, oxobenzothiazolinyl,
benzoisothiazolyl, oxobenzoisothiazolinyl, benzoimidazolyl,
oxobenzoimidazolinyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, imidazopyridyl,
oxodihydroimidazopyridyl, quinolyl, isochinolinyl,
dihydroquinolinyl, oxodihydroquinolinyl, tetrahydroquinolinyl,
oxotetrahydroquirclinyl, carbazolyl, tetrahydrocarbazolyl,
pyridoindolyl, acridinyl, oxodihydroacridinyl, phenanthridinyl,
dihydrophenanthridinyl, oxodihydrophenanthridinyl,
dihydrobenzoisoquinolinyl, oxodihydrobenzoisoqu inolinyl,
phenothiazinyl, dihydrodibenzooxepinyl, benzocycloheptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
dibenzoazepinyl, dihydrodibenzoazepinyl, oxodihydrodibenzoazepinyl,
benzocycloheptapyridyl, oxodihydrobenzocycloheptapyridyl,
pyridobenzoazepinyl, dihydropyridobenzoazepinyl,
oxodihydropyridobenzoazepinyl, dihydropyridobenzodiazepinyl,
oxodihydropyridobenzodiazepinyl, dihydrodibenzooxazepinyl,
dihydropyridobenzooxazepinyl, dihydrodibenzothiazepinyl or
dihydropyridobenzothiazepinyl; R.sup.14 is selected from hydrogen,
methyl, benzyl, phenyl; R.sup.15 is selected from hydrogen,
hydroxy, methyl, benzyl, phenyl, indanyl, inaenyl, naphthyl,
tetrahydronaphthyl, furyl, thienyl, pyridyl, pyrazinyl,
pyridazinyl, pyrimidinyl, benzofuryl, benzothienyl, indolyl,
indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl
or tetrahydroquinolinyl; R.sup.16 is selected from hydrogen,
C.sub.1 -C.sub.4 -alkyl, benzyl and phenyl; Ar.sup.1 and Ar.sup.2
are selected independent from each other from phenyl, pyridyl or
naphthyl; and the grouping .dbd.(C).sub.u R.sup.13 R.sup.15 is
selected from indanyl, tetrahydronaphthyl, fluorenyl,
tetrahydrobenzocycloheptenyl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl; tetrahydroquinolinyl,
dihydrodibenzooxepinyl, dihydrothienobenzothiepinyl,
dihydrodibenzothiepinyl, dibenzoazepinyl, dihydrodibenzoazepinyl,
benzocycloheptapyridinyl, dihydrobenzocycloheptapyridinyl
pyridobenzoazepinyl, dihydropyridobenzoazepinyl; and the grouping
ER.sup.13, R.sup.15 represents a spirocycle selected from
dioxaazaspirodecane, dithiaazaspirodecane, diazaspirodecanone,
diazaspirodecandione, triazaspirodecanone, triazaspiro-decandione,
dioxaazaspiroundecane, dithiaazaspiroundecane,
oxadiazaspiroundecanone, triazaspiroundecanone,
spiro[benzo-dioxol-pyrrolidin], spiro[benzodioxol-piperidine],
spiro-[benzodioxin-piperidine], spiro
[dihydrobenzoxazin-piperi-dine]; and whereby the grouping
--NR.sup.13 R.sup.15 represents a ring of heterocycle bound over
the nitrogen atom selected from the following: piperidine,
hexahydroazepine, piperazine hexahydrodiazepine, morpholine,
thiomorpholine, indoline, isoindoline, (1H)-dihydroquinoline,
(1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline,
(4H)-dihydrobenzooxazine, (4H)-dihydrobenzothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,
(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydro-benzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine, carbazole,
(10H)-dihydroacridine, (10H)-dihydrophenanthridine,
(5H)-dibenzoazepine, (5H)-dihydrodibenzoazepine,
(5H)-dihydrodibenzodiazepine, (5H)-benzo[b]pyrido[f]azepine,
(5H)-dihydrobenzo[b]pyrido[f]azepine,
(11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine,
(11H)-dihydrobenzo[e]pyrido[b]-1,4-diazepin-6-one or
(11H)-dihydrobenzo[b]pyrido[e]-1,4-diazepin-5-one, whereby the ring
systems .dbd.CR.sup.13 R.sup.15, --NR.sup.13 R.sup.15 and
optionally ER.sup.13, R.sup.15 as well as aromatic ring systems in
the substituents R.sup.1, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
Ar.sup.1 and Ar.sup.2 can be substituted independently of each
other by one to three of the same or different groups selected from
halogen, cyano, C.sub.1 -C.sub.6 -Alkyl, trifluoromethyl, C.sub.3
-C.sub.8 -cycloalkyl, phenyl, benzyl, hydroxy, C.sub.1 -C.sub.6
-hydroxyalkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkoxy
entirely or partially substituted by benzyloxy, phenoxy, mercapto,
C.sub.1 -C.sub.6 -alkylthio, carboxy, C.sub.2 -C.sub.7
-carboxyalkyl, C.sub.2 -C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7
-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C.sub.1
-C.sub.6 -alkylamino, Di-(C.sub.1 -C.sub.6 -alkyl)-amino and, for
two adjacent residues on the aromatic ring, methylenedioxy, and
whereby alkyl-, alkenyl- and cycloalkyl residues in the groups G
can be substituted by one or two of the same or different groups
selected from hydroxy, carboxy, C.sub.2 -C.sub.7 -alkoxycarbonyl,
benzyloxycarbonyl, amino, mono-C.sub.1 -C.sub.6 -alkylamino and
di-(C.sub.1 -C.sub.6 -alkyl)-amino.
According to a further particular embodiment, the invention relates
to new compounds of the general formula (I) ##STR26## R.sup.1 is
selected from hydrogen, fluorine, methyl, trifluoromethyl
ethylthio; R.sup.2, R.sup.3 and R.sup.4 are each hydrogen; k has
the meaning 0, A is selected from ethylene, propylene or butylene
optionally substituted by hydroxy or one or two fluorine atoms; or
OCH.sub.2 or SCH.sub.2 ; ethenylene, or 1,3-butadienylene; D is
selected from C.sub.4 -C.sub.6 -alkylene which is optionally
substituted by hydroxy; C.sub.4 -C.sub.6 alkenylene; C.sub.4
-C.sub.6 alkinylene; or C.sub.4 -C.sub.6 alkylene, C.sub.4 -C.sub.6
alkenylene or C.sub.4 -C.sub.6 alkinylene, wherein one or two
methylene units is isosterically replaced by O, NH, CO or SO.sub.2
; E is piperidine G is selected from diphenylmethyl,
diphenylhydroxymethyl, diphenylmethylene, naphthyl,
tetrahydronaphthyl, tetrahydronaphthylidene, flqoroenyl,
fluorenylidene, tetrahydrobenzocycloheptenyl or
tetrahydrobenzocycloheptenylidene, dihydrodibenzoycloheptenyl or
dihydrodibenzocycloheptenylidene; mixed diphenyl;
phenyl-thienylmethyl, phenyl-thienylmethylene,
phenyl-pyridylmethyl, phenyl-pyridylmethylene,
tetrahydroquinolinyl, tetrahydroisoguinolinyl,
benzocycloheptapyridinyl, benzocycloheptapyridinylidene,
dihydrobenzocycloheptapyridinyl,
dihydrobenzocycloheptapyridinylidene, dihydrodibenzooxepinyl,
dihydrodibenzooxepinylidene, dihydrodibenzothiepinyl,
Dihydrodibenzothiepinylidene, Dihydrobenzothienothiepinyl or
dihydrobenzothienothiepinylidene; indolyl, oxobenzoimidazolyl,
oxobenzothiazolyl, benzoisothiazolyl or benzotriazolyl;
dibenzylaminocarbonyl, diphenylaminocarbonyl, indolinyl-N-carbonyl,
isoindolinyl-N-carbonyl, tetrahydroquinolinyl-N-carbonyl,
tetrahydrobenzoazepinyl-N-carbonyl, carbazolyl-N-carbonyl,
dihydrodibenzoazepinyl-N-carbonyl or
oxodihydrobenzopyridodiazepinyl-N-carbonyl; diphenylmethylamino,
diphenylmethyl-methylamino, dibenzylamino, benzylphenylamino or
triphenylmethylamino; acetylamino, pivaloylamino,
phenylacetylamino, diphenylacetylamino, diphenylpropionylamino,
naphthylacetylamin, benzoylamino, benzoylmethylamino,
naphthoylamino or oxofluorenylcarbonylamino; furoylamino,
pyridylacetylamino or pyridyicarbonylamino;
benzylaminocarbonylamino, naphthylmethylaminocarbonylamino,
indanylaminocarbonylamino, tetrahydronaphthylaminocarbonyl,
dibenzylaminocarbonylamino, phenylylaminocarbonylamino,
naphthylaminocarbonylamino, benzylphenylaminocarbonylamino or
diphenylaminocarbonylamino; indolinyl-N-carbonylamino,
isoindolinyl-N-carbonylamino, tetrahydraquinolinyl-N-carbonylamino,
tetrahydrobenzoazepinyl-N-carbonylamino,
carbazolyl-N-carbonylamino, dihydrophenanthridinyl-N-carbonylamino,
dihydrodibenzoazepin-N-carbonylamino,
dihydrobenzopyridoazepinyl-N-carbonylamino or
oxodihydrobenzopyridodiazepinyl-N-carbonylamino;
methanesulfonylamino, tolylsulfonylamino, naphthylsulfonylamino or
diphenylphosphinoylamino; diphenylmethyloxy or
diphenylphosphinoyloxy, whereby aromatic ring systems can be
substituted independently of each other by one to three of the same
or different groups selected from halogen, cyano, C.sub.1 -C.sub.6
-alkyl, trifluoromethyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl,
benzyl, hydroxy, C.sub.1 -C.sub.6 -hydroxyalkyl, C.sub.1 -C.sub.6
-alkoxy, C.sub.1 -C.sub.6 -alkoxy entirely or partially substituted
by fluorine, benzyl-oxy, phenoxy, mercapto, C.sub.1 -C.sub.6
-alkylthio, carboxy, C.sub.2 -C.sub.7 -carb-oxyalkyl, C.sub.2
-C.sub.7 -carboxyalkenyl, C.sub.2 -C.sub.7 -alkoxycarbonyl,
benzyl-oxycarbonyl, nitro, amino, mono-C.sub.1 -C.sub.6
-alkylamino, di-(C.sub.1 -C.sub.6 -al-kyl)-amino and, for two
adjacent residues on the aromatic ring, methylenedioxy, and whereby
alkyl-, alkenyl- and cycloalkyl residues in the group G can be
substituted by one or two of the same or different groups selected
from hydroxy, carboxy, C.sub.2 -C.sub.7 -alkoxycarbonyl,
benzyloxycarbonyl, amino, mono-C.sub.1 -C.sub.6 -alkylamino and
di-(C.sub.1 -C.sub.6 -alkyl)amino;
In the following, a series of compounds with the respective
specific substituent definitions are listed in Table 1 without any
limitation for further illustration of the compounds according to
the invention.
TABLE 1 Exemplifying compounds of formula (I) according to the
invention ##STR27## Nr R.sup.1 --R.sup.3 k A R.sup.4 D--E--G 1 H 0
CH.dbd.CH H ##STR28## 2 H 0 CH.dbd.CH H ##STR29## 3 H 0 CH.sub.2
CH.sub.2 H ##STR30## 4 H 0 CH.sub.2 CH.sub.2 H ##STR31## 5 H 0
CH.dbd.CH H ##STR32## 6 H 0 CH.dbd.CH H ##STR33## 7 H 0 CH.dbd.CH H
##STR34## 8 H 0 CH.sub.2 CH.sub.2 H ##STR35## 9 H 0 CH.sub.2
CH.sub.2 H ##STR36## 10 H 0 CH.dbd.CH H " 11 H 0 CH.dbd.CH H
##STR37## 12 H 0 CH.dbd.CH H ##STR38## 13 H 0 CH.dbd.CH H ##STR39##
14 H 0 OCH.sub.2 H " 15 H 0 CH.sub.2 CH.sub.2 H ##STR40## 16 H 0
CH.dbd.CH H " 17 H 0 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H
##STR41## 18 H 0 CH.dbd.CH H ##STR42## 19 H 0 CH.dbd.CH--CH.dbd.CH
H ##STR43## 20 H 0 CH.dbd.CH H ##STR44## 21 H 0 CH.sub.2 CH.sub.2 H
##STR45## 22 H 0 CH.sub.2 CH.sub.2 H ##STR46## 23 H 0 CH.dbd.CH H "
24 H 0 OCH.sub.2 H ##STR47## 25 H 0 CH.sub.2 CH.sub.2 H ##STR48##
26 H 0 SCH.sub.2 H ##STR49## 27 H 0 ##STR50## H " 28 H 0 ##STR51##
H " 29 H 0 CH.dbd.CH H ##STR52## 30 H 0 CH.sub.2 CH.sub.2 H
##STR53## 31 H 0 CH.dbd.CH H " 32 H 0 CH.dbd.CH H ##STR54## 33 H 0
CH.dbd.CH H ##STR55## 34 H 0 CH.dbd.CH H ##STR56## 35 H 0 CH.dbd.CH
H ##STR57## 36 H 0 OCH.sub.2 H ##STR58## 37 H 0 C.ident.C H " 38 H
0 CH.dbd.CH H ##STR59## 39 H 0 CH.dbd.CH--CH.dbd.CH H ##STR60## 40
H 0 CH.sub.2 CH.sub.2 H ##STR61## 41 H 0 ##STR62## H " 42 H 0
CH.dbd.CH--CH.dbd.CH H " 43 H 0 CH.dbd.CH H ##STR63## 44 H 0
CH.sub.2 CH.sub.2 H ##STR64## 45 H 0 CH.dbd.CH H ##STR65## 46 H 0
OCH.sub.2 H ##STR66## 47 H 0 CH.sub.2 CH.sub.2 H ##STR67## 48 H 0
OCH.sub.2 H ##STR68## 49 H 0 CH.dbd.CH H ##STR69## 50 H 0 CH.sub.2
CH.sub.2 H ##STR70## 51 H 0 CH.dbd.CH H " 52 H 0 CH.dbd.CH H
##STR71## 53 H 0 CHFCH.sub.2 H ##STR72## 54 H 0 CH.dbd.CH H
##STR73## 55 H 0 CH.dbd.CH H ##STR74## 56 H 0 OCH.sub.2 H " 57
6-C.sub.2 H.sub.5 S 0 CH.dbd.CH H ##STR75## 58 H 0 CH.dbd.CH H
##STR76## 59 H 0 CH.dbd.CH H ##STR77## 60 H 0 CH.dbd.CH H ##STR78##
61 H 1 CH.dbd.CH H " 62 2-Cl 0 CH.dbd.CH H " 63 6-CH.sub.3 0
CH.dbd.CH H " 64 H 0 ##STR79## H " 65 H 0 SCH.sub.2 H " 66 H 0
##STR80## H " 67 H 0 CH.sub.2 CH.sub.2 H ##STR81## 68 H 0 CH.dbd.CH
H ##STR82## 69 H 0 CH.sub.2 CH.sub.2 H ##STR83## 70 H 0 CH.dbd.CH H
##STR84## 71 H 0 CH.sub.2 CH.sub.2 H ##STR85## 72 H 0 CH.dbd.CH H "
73 6-C.sub.6 H.sub.5 S 0 CH.dbd.CH H " 74 H 0 ##STR86## H " 75 H 0
##STR87## H " 76 H 0 ##STR88## H " 77 H 0 CH.dbd.CH CH.sub.3
##STR89## 78 H 0 CH.dbd.CH H ##STR90## 79 H 0 CH.dbd.CH H ##STR91##
80 H 0 ##STR92## H ##STR93## 81 H 0 ##STR94## H ##STR95## 82 H 0
CH.dbd.CH H " 83 H 1 CH.dbd.CH H " 84 2,6- 0 CH.dbd.CH H "
(CH.sub.3).sub.2 85 H 0 C.ident.C H " 86 H 0 CH.dbd.CH H ##STR96##
87 6-CH.sub.3 0 CH.dbd.CH H " 88 H 0 OCH.sub.2 H " 89 H 0 CH.dbd.CH
H ##STR97## 90 H 0 CH.dbd.CH H ##STR98## 91 H 0 CH.dbd.CH H
##STR99## 92 H 0 CH.dbd.CH H ##STR100## 93 H 0 CH.dbd.CH H
##STR101## 94 H 0 CH.sub.2 CH.sub.2 H ##STR102## 95 H 0 CH.sub.2
CF.sub.2 H ##STR103## 96 H 0 OCH.sub.2 H " 97 H 0 CH.dbd.CH H
##STR104## 98 H 0 CH.dbd.CH H ##STR105## 99 H 0 OCH.sub.2 H
##STR106## 100 H 0 SCH.sub.2 H " 101 H 0 C.ident.C H " 102 H 0
CH.dbd.CH H ##STR107## 103 H 0 CH.sub.2 CH.sub.2 H ##STR108## 104 H
0 CH.dbd.CH H " 105 H 0 CH.dbd.CH H ##STR109## 106 H 0 CH.dbd.CH H
##STR110## 107 5-F 0 CH.dbd.CH H ##STR111## 108 H 0 CH.dbd.CH
C.sub.2 H.sub.5 " 109 H 0 CH.dbd.CH H ##STR112## 110 H 0 CH.sub.2
CH.sub.2 H ##STR113## 111 H 0 ##STR114## H " 112 H 0 CH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 H " 113 H 0 CH.dbd.CH H ##STR115## 114 H
1 CH.dbd.CH H " 115 H 0 SCH.sub.2 H " 116 H 0 CH.dbd.CH H
##STR116## 117 H 0 CH.sub.2 CH.sub.2 H ##STR117## 118 H 0 CH.dbd.CH
H " 119 H 0 ##STR118## H " 120 H 0 CH.dbd.CH H ##STR119## 121 H 0
CH.sub.2 CH.sub.2 H ##STR120## 122 H 0 CH.sub.2 CH.sub.2 H
##STR121## 123 H 0 CH.dbd.CH H ##STR122## 124 H 0 CH.dbd.CH H
##STR123## 125 H 0 CH.sub.2 CH.sub.2 H ##STR124## 126 H 0 CH.dbd.CH
H ##STR125## 127 H 0 CH.dbd.CH--CH.dbd.CH H ##STR126## 128 H 0
CH.dbd.CH H ##STR127## 129 6-C.sub.6 H.sub.5 O 0 CH.dbd.CH H " 130
H 0 CH.dbd.CH H ##STR128## 131 H 0 CH.dbd.CH H ##STR129## 132 H 0
OCH.sub.2 H ##STR130## 133 H 0 CH.dbd.CH H ##STR131## 134 H 0
CH.dbd.CH H ##STR132## 135 H 0 CH.dbd.CH H ##STR133## 136 H 0
CH.sub.2 CH.sub.2 H ##STR134## 137 H 0 CH.dbd.CH--CH.dbd.CH H " 138
H 0 CH.dbd.CH H ##STR135## 139 H 0 CH.dbd.CH H ##STR136##
140 H 0 CH.dbd.CH H ##STR137## 141 H 0 OCH.sub.2 H ##STR138## 142 H
0 CH.dbd.CH H ##STR139## 143 H 0 ##STR140## H ##STR141## 144 H 0
CH.sub.2 CH.sub.2 H ##STR142## 145 H 0 CH.dbd.CH H " 146 H 0
CH.sub.2 CH.sub.2 H ##STR143## 147 H 0 CH.dbd.CH H " 148 H 0
CH.dbd.CH H ##STR144## 149 H 0 CH.dbd.CH H ##STR145## 150 H 0
CH.dbd.CH H ##STR146## 151 H 0 CH.dbd.CH CH.sub.3 ##STR147## 152 H
0 CH.sub.2 CH.sub.2 H ##STR148## 153 H 0 CH.dbd.CH H ##STR149## 154
H 0 CH.dbd.CH H ##STR150## 155 H 0 ##STR151## H ##STR152## 156 H 0
CH.dbd.CH H ##STR153## 157 H 0 ##STR154## H ##STR155## 158 H 0
CH.dbd.CH--CH.dbd.CH H ##STR156## 159 H 0 CH.sub.2 CH.sub.2 H
##STR157## 160 H 0 CH.dbd.CH H ##STR158## 161 H 0 CH.sub.2 CH.sub.2
H ##STR159## 162 H 0 C.ident.C H ##STR160## 163 H 0 CH.dbd.CH H
##STR161## 164 H 0 ##STR162## H " 165 H 0 CH.dbd.CH H ##STR163##
166 H 0 OCH.sub.2 H " 167 H 0 CH.sub.2 CH.sub.2 H ##STR164## 168 H
0 CH.dbd.CH H " 169 H 0 CH.dbd.CH H ##STR165## 170 H 0 CH.dbd.CH H
##STR166## 171 H 0 CH.dbd.CH H ##STR167## 172 H 0 CH.sub.2 CH.sub.2
H ##STR168## 173 H 0 CH.dbd.CH H " 174 H 0 SCH.sub.2 H " 175 H 0
CH.dbd.CH H ##STR169## 176 H 0 CH.dbd.CH H ##STR170## 177 H 0
CH.dbd.CH--CH.dbd.CH H " 178 H 0 CH.dbd.CH H ##STR171## 179 H 0
CH.sub.2 CH.sub.2 H ##STR172## 180 H 0 ##STR173## H ##STR174## 181
H 0 OCH.sub.2 H ##STR175## 182 H 0 ##STR176## H " 183 H 0 CH.dbd.CH
H ##STR177## 184 H 0 CH.dbd.CH H ##STR178## 185 H 0 CH.sub.2
CH.sub.2 H ##STR179## 186 H 0 CH.dbd.CH H ##STR180## 187 H 0
CH.sub.2 CH.sub.2 H ##STR181## 188 H 0 CH.dbd.CH H " 189 H 0
CH.dbd.CH H ##STR182## 190 H 0 CH.dbd.CH H ##STR183## 191 H 0
CH.dbd.CH H ##STR184## 192 H 0 CH.dbd.CH H ##STR185## 193 H 0
CH.dbd.CH H ##STR186## 194 H 0 CH.sub.2 CH.sub.2 H ##STR187## 195 H
0 OCH.sub.2 H ##STR188## 196 H 0 CH.sub.2 CH.sub.2 H ##STR189## 197
H 0 CH.dbd.CH H ##STR190## 198 H 0 CH.dbd.CH H ##STR191## 199 H 0
CH.dbd.CH H ##STR192## 200 H 0 OCH.sub.2 H " 201 H 0 CH.dbd.CH H
##STR193## 202 H 0 CHFCH.sub.2 H ##STR194## 203 H 0 CH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 H ##STR195## 204 H 0 CH.dbd.CH H
##STR196## 205 H 0 CH.dbd.CH H ##STR197## 206 H 0 CH.dbd.CH H
##STR198## 207 H 0 CH.sub.2 CH.sub.2 H ##STR199## 208 H 0 CH.dbd.CH
H ##STR200## 209 H 0 CH.dbd.CH--CH.dbd.CH H ##STR201## 210 H 0
CH.dbd.CH H ##STR202## 211 H 0 CH.dbd.CH H ##STR203## 212 H 0
CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 H " 213 H 0 CH.sub.2 CH.sub.2 H
##STR204## 214 H 0 CH.dbd.CH H " 215 H 0 CH.dbd.CH H ##STR205## 216
H 0 CH.dbd.CH H ##STR206## 217 H 0 CH.sub.2 CF.sub.2 H ##STR207##
218 H 0 CH.dbd.CH H ##STR208## 219 H 0 CH.sub.2 CH.sub.2 H
##STR209## 220 H 0 CH.dbd.CH H ##STR210## 221 H 0 CH.dbd.CH H
##STR211## 222 H 0 CH.dbd.CH H ##STR212## 223 H 0 CH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 H ##STR213## 224 H 0 CH.dbd.CH H ##STR214## 225 H
0 OCH.sub.2 H ##STR215## 226 H 0 CH.dbd.CH H ##STR216## 227 H 0
SCH.sub.2 H ##STR217## 228 H 0 CH.sub.2 CH.sub.2 H ##STR218## 229 H
0 CH.dbd.CH H " 230 H 0 CH.dbd.CH H ##STR219## 231 H 0 CH.dbd.CH H
##STR220## 232 H 0 CH.sub.2 CH.sub.2 H ##STR221## 233 H 0 CH.dbd.CH
H ##STR222## 234 H 0 CH.dbd.CH H ##STR223## 235 H 0 CH.sub.2
CH.sub.2 H ##STR224## 236 H 0 CH.dbd.CH H " 237 H 0 CH.dbd.CH H
##STR225## 238 H 0 CH.sub.2 CH.sub.2 H ##STR226## 239 H 0 CH.dbd.CH
H ##STR227## 240 H 0 CH.dbd.CH H ##STR228## 241 H 0 CH.dbd.CH H
##STR229## 242 H 0 CH.dbd.CH H ##STR230## 243 H 0 CH.sub.2 CH.sub.2
H ##STR231##
Further subject-matter of the claims are analogous methods for the
production of the compounds of formula (I) according to the
invention.
According to method variant (A), compounds of formula (I) are
obtained in the manner by reacting carboxylic acids of formula (II)
##STR232##
in which R.sup.1, R.sup.2, R.sup.3, A and k have the meaning given
above or their reactive derivatives with compounds of formula (III)
##STR233##
wherein D, E, G and R.sup.4 are defined as above.
Reactive derivatives of compound (II) can be, for example,
activated esters, anhydrides, acid halides (especially acid
chlorides) or simple low alkyl esters. Suitable activated esters
are, for example, p-nitrophenyl ester, 2,4,6-trichlorphenyl ester,
pentachlorophenyl ester, cyanomethyl ester, esters of
N-hydroxysuccinimide, N-hydroxyphthalimides,
1-hydroxybenzotriazole, N-hydroxypiperidine, 2-hydroxypyridine or
2-mercaptopyridine, etc.
Anhydrides can be symmetric anhydrides or mixed, as they are
obtained, for example, with pivaloyl chloride or with
chloroformates. Aromatic (for example chloroformic phenyl ester),
araliphatic (for example chloroformic benzyl ester) or aliphatic
chloroformates (for example chloroformic methyl ester, ethyl ester
or isobutyl ester) can be used for this.
Reaction of the compounds of formula (II) with the compounds of
formula (III) can also be carried out in the presence of
candensation agents such as dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminpropyl)carbodiimide.hydrochloride,
N,N'-carbonyldiimidazole,
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc. If
carbodiimides are used as the condensation agent, reagents such as
N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole,
N-hydroxypiperidine, etc. can be advantageously added.
Compounds of formula (III) can be used for reaction as free bases
as well as in the form of their acid addition salts. For this, the
salts of inorganic acids are to be preferred, i.e. hydrochlorides,
hydrobromides or sulfates for example.
Reaction of compounds (II) or their reactive derivatives with
compounds (III) are normally carried out in a suitable, preferably
inert solvent. As examples, aromatic hydrocarbons such as benzene,
toluene, xylene, halogenated hydrocarbons (for example
dichloromethane, chloroform, 1,2-dichloroethane,
trichloroethylene), or ethers such as for example diethyl ether,
tetrahydrofuran, dioxane, glycol dimethyl ether, ethyl acetate,
acetonitrile or polar aprotic solvents such as, for example,
dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to
be named. Pure solvents, as well as mixtures of two or more, can be
used.
The reaction is optionally carried out in the presence of an
auxiliary base. Suitable examples for this are alkali metal
carbonates such as sodium carbonate or potassium carbonate, alkali
metal hydrogen carbonates such as sodium hydrogen carbonate or
potassium hydrogen carbonate or organic bases such as, for example,
triethylamine, ethyl diisopropylamine, tributylamine,
N-metbylmorpholine or pyridine. A suitable excess of the compound
of formula (III) can also be used as a base. If compounds of
formula (III) are used in form of their acid addition salts, then
it is appropriate to consider the amount of auxiliary base used as
equivalent.
The reaction temperatures can--depending on reactivity of the
starting materials--vary in a wide range. Generally, the reaction
is carried out at temperatures between -40.degree. C. and
180.degree. C., preferably between -10.degree. C. and 130.degree.
C., especially at the boiling point of the solvent used.
The starting compounds (II) and (III) are known and/or can be
produced according to known methods in an analogous manner.
Moreover, the production of representative examples is described
below.
Additionally, compounds of formula (I) wherein G corresponds to the
definitions G4a to G4e can also be produced according to the
variant pursuant to Method B by reacting compounds of formula (I)
wherein G.dbd.NHR.sup.16, and which themselves represent active
ingredients according to the invention with suitable alkylation or
arylation agents and/or carboxylic acid, carboxaminic acid,
sulfonic acid or phosphinic acid derivatives of the formula (IVa)
to (IVe) ##STR234##
wherein L signifies respectively a suitable nucleofuge. The type of
nucleofuge L and the conditions of the reaction are dependent of
the nature of the residue to be transferred.
By means of method variant (B1), compounds of formula (I), in which
G, with the exception of NHR.sup.16, has the meaning of G4a
according to the above definition can also be synthesized by
reacting compounds of formula (I), in which G is NHR.sup.16, with a
suitable alkylation agent and/or arylation agent of formula (IIVa),
wherein r, s, R.sup.13, R.sup.14, and R.sup.15, are defined above
and the leaving group L can be a reactive derivative of an alcohol,
for example, a halogen atom such as chlorine, bromine or iodine or
a sulfonic acid ester, i.e. for example a methanesulfonyloxy group,
trifluoromethanesulfonyloxy-, ethanesulfonyloxy-,
benzenesulfonyloxy-, p-toluenesulfonyloxy-,
p-bromobenzenesulfonyloxy-, m-nitrobenzenesulfonyloxy group.
The reaction of compounds of formula (I), in which G is the residue
NHP.sup.16 with the compounds of formula (IVa) is usually conducted
in a suitably inert solvent. Such solvents can be for example the
following: aromatic hydrocarbons such as benzene, toluene, xylene;
ethers such as for example tetrahydrofuran, dioxane, glycol
dimethyl ether, ethyl acetate or acetonitrile, ketones such as
acetone or ethyl methyl ketones, polar protic solvents such as
alcohols for example ethanol, isopropanol or butanol or also glycol
monomethyl ether; or polar aprotic solvents such as, for example,
dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Pure
solvents as well as mixtures of two or more can also be used.
Preferably, the reactions are carried out in the presence of bases,
whereby the same bases as named in method variant (A) above can be
used. If chlorides or bromides are used as the compound of formula
(IVa), the reaction can be accelerated in this manner by the
addition of alkali metal iodides such as sodium iodide or potassium
iodide. The reaction temperatures can vary between 0.degree. C. and
180.degree. C. depending on the reactivity of the educts, but
preferably lie between 20.degree. C. and 130.degree. C.
According to the method variant (B2), compounds of formula (I), in
which G has the meaning of G4b to G4e according to the above
definition, can also be produced by reacting compounds of formula
(I), wherein G is the residue NHR.sup.16, with a carboxylic acid,
carbamic acid, sulfonic acid and/or phosphinic acid of formula (Vb)
to (Ve) wherein r, s, R.sup.13, R.sup.14, R.sup.15, Ar.sup.1,
Ar.sup.2 and optionally the group NR.sup.13 R.sup.15 have the
present meanings, ##STR235##
or their derivatives capable of reaction. Preferred derivatives of
carboxylic acids according to formulas (Vb) and (Vc) and/or
sulfonic acids of formula (Vd) which are capable of reaction are
representatives of symmetric or unsymmetric carboxylic acid
anhydrides and/or sulfonic acid anhydrides or carboxylic halides
and/or sulfonyl halides, especially carboxylic and/or sulfonyl
chlorides. Preferred derivatives of carbamates according to formula
(Vc), wherein r=0, and/or phosphinic acids of formula (Ve) which
are capable of reaction are the carbamoyl halides and/or phosphinyl
halides, especially carbamyl- and/or phosphinyl chlorides. The
reaction of the acids according to formula (V) and/or their
reactive derivatives with compounds of formula (I), in which G is
the residue NHR.sup.16, preferably occurs in the presence of
auxiliary bases in solvents and under conditions as they are
described in method variant (A).
Compounds of formula (I), wherein G represents a carbamoyl residue
according to the definition (G4c) with r=0, i.e. a group
##STR236##
can also be produced aside according to variants (A) and (B2),
pursuant to the variant method (B3) by reacting compounds of
formula (I), in which G represents the residue NHR.sup.1 6, with a
carbonyl group transmitter to an intermediate product and
subsequently reacting this directly with a primary or secondary
amine with the formula (VI)
wherein the residues R.sup.13 and R.sup.15 have the meanings
according to the above definitions without purifying or isolating
the intermediate product.
Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazole
have been proven as particularly reactive carbonyl group
transmitters. The reaction of compounds of formula (I), wherein G
is residue NHR.sup.16, with triphosgene and/or carbonyldiimidazole
are typically conducted in an absolute, inert solvent in the
presence of a tertiary organic amine as an auxiliary base in such a
manner that the solution of compounds (I) and the auxiliary base
are slowly poured into a solution of an equivalent amount of
carbonyl group transmitter. Thereby, the reaction requires molar
ratios of 1:1 for the reaction of compound (I) and
carbonyldiimidazole, and, in contrast, a ratio of 1:0.35 for the
use of triphosgene. After complete reaction of the components to
the intermediate product, compound (VI) is added in stochiometric
amounts or in excess as a solution or a solid and the reaction is
typically completed at elevated temperature. Suitable inert
solvents are, for example hydrocarbons such as hexane, heptane,
benzene, toluene, xylene, chlorinated hydrocarbons such as for
example dichloromethane, chloroform, 1,2-dichloroethane or
trichloroethylene, ethers such as for example diethyl ether,
tetrahydrofuran or dioxane, esters such as ethyl acetate, butyl
acetate, acetonitrile; or polar aprodic solvents such as formamide
or dimethylformamide. Pure solvents as well as mixtures of various
solvents can be used. Amines such as for example triethylamine,
ethyl diisopropylamine, tributylamine, N-methylmorpholine or
pyridine are suitable as auxiliary bases.
If the compounds or formula (I) or formula (VI) are used as salts,
the amount of the auxiliary base is increased accordingly. The
reaction temperatures can lie between -40.degree. C. and 50.degree.
C. for the first partial reaction, preferably 0.degree. C. to
30.degree. C., and between 0.degree. C. and 150.degree. C. for the
second partial reaction, preferably 20.degree. C. to 120.degree.
C.
According to method variant pursuant (B4), compounds of formula
(I), wherein G represents a carbamoyl residue according to the
definition (G4c) with r=0 and R.sup.15 hydrogen, i.e. the group
##STR237##
can also be produced, aside according to variants (A), (B2) and
(B3), by reacting the compounds of formula (I) in which G is the
residue NHR.sup.16, with an isocyanate of formula (VII)
O.dbd.C.dbd.N--R.sup.13 (VII).
in which R.sup.13 has the above defined meaning
Reaction of the compounds of formula (I), in which G is the residue
NHR.sup.16, with the isocyanates of formula (VII) are conducted
thereby in absolute, inert solvents as they are named above in
method (B3). Mixtures of various solvents can also be used.
Thereby, the reaction temperatures can vary in the region from
-20.degree. C. to 150.degree. C., but preferably lie at 20.degree.
C. to 100.degree. C.
As already mentioned, the compounds of formula (I), wherein G
represents the residue NHR.sup.16, are themselves active
ingredients according to the invention with tumor growth inhibiting
activity. However, independent of their therapeutic applicability,
they also represent useful intermediate compounds for the
production of a multitude of other compounds according to the
invention corresponding to the method variants (B1) to (B4).
In principle, they themselves, can be produced according to method
A by reacting a carboxylic acid of formula (II) with amines of
formula (III) in which G is the residue NHR.sup.16 as. described
above. However, since the compounds of formula (III) with
NHR.sup.16 as G represent .alpha., .omega.-diamines, the formation
of product mixtures is always to be expected in their reaction with
carboxylic acids (II). In this case, this makes a subsequent
separation necessary.
In contrast, compounds of formula (I), in which G is the residue
NHR.sup.16, are essentially more advantageously produced from other
compounds of formula (I), in which G, within the meaning of G4, is
a selectively cleavable group under mild conditions which
corresponds to a nitrogen protective group.
In this connection, among the compounds according to formula (I)
with the named pharmacological properties, compounds in which the
nitrogen atom of G4 carries, aside from the residue R.sup.16, G a
benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a
triphenylmethyl group, a benzyloxy-carbonyl group, a methoxy-
and/or ethoxycarbonyl group, a tert-butoxycarbonyl group, an
allyloxycarbonyl group or a trifluoroacetyl group are particularly
suitable. Thus, compounds of formula (I) with NR.sup.16 -benzyl,
NR.sup.16 -diphenylmethyl, NR.sup.16 -triphenylmethyl or NR.sup.16
-benzyloxycarbonyl groups as G can already be catalytically
transformed into compounds of formula (I) with NHR.sup.16 as G at
room temperature under mild conditions with elementary hydrogen or
by transfer hydration. Compounds of formula (I) with a NR.sup.16
-(4-methoxybenzyl) group are converted to compounds of formula (I)
with NHR.sup.16 as G by selective oxidation with
ammonium-cer(IV)-nitrate. The cleavage of simple NR.sup.16
-alkoxycarbonyl groups such as the methoxy - or ethoxycarbonyl
group as well as the NR.sup.16 -trifluoroacetyl group as G in
compounds of formula (I) succeed by alkali hydrolysis under mild
conditions without cleaving the A and D linked amide function. This
is suitably valid for the cleavage of the NR.sup.16
-triphenylmethyl group and the NR.sup.16 -tert-butoxycarbonyl group
as G in compounds of formula (I) which occurs in acidic medium
under mild conditions. Finally, compounds of formula (I) with an
NR.sup.16 -allyloxycarbonyl group as G can be converted into such
with NHR.sup.16 G in neutral medium with palladium catalyst.
All these methods are fully familiar to the person skilled in the
art, and are furthermore also documented in various monographs, see
for example Greene, Wuts: Protective Groups in Organic Synthesis,
New York, 1991.
The compounds of formula (I) produced according to the methods (A)
to (B) can be isolated and purified in a known manner, for example
by subjecting the residue after distillation of the solvent to
partition, extraction, re-precipitation or re-crystallization or
another purification method. For this, column chromatography on a
suitable support or preparative middle or high pressure liquid
chromatography (HPLC) are preferred for this.
The compounds (I) are first normally obtained in form of their free
bases or their hydrates or solvates, depending on the type of
isolation and purification. Their addition salts with
pharmaceutically suitable acids are obtained in a typical manner by
converting the base with the desired acid in a suitable solvent.
Depending on the number of basic centers of compounds (I), one or
more equivalent acids per mole of base can be bound.
Suitable solvents are, for example, chlorinated hydrocarbons such
as dichloromethane or chloroform; ethers such as diethyl ether,
dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone
or ethyl methyl ketone; esters such as methyl acetate or ethyl
acetate or low molecular alcohols such as methanol, ethanol or
isopropanol; as well as water. Pure solvents as well as mixtures of
two or three solvents can also be used. The salts can be isolated
by crystallization, precipitation or the evaporation of the
solvent. Thereby, they optionally accumulate as hydrates or
solvates.
The bases can be recovered from the salts by alkalization, for
example with aqueous ammonia solution, alkali carbonate or diluted
sodium hydroxide solution.
In the following, a series of compounds, according to the invention
as well as the following synthetic examples are given for
illustration of the above methods:
SYNTHETIC EXAMPLES
For the End Products of the Invention According to Formula (I)
In the production examples for the end products, the abbreviations
stand for the following terms: MP=melting point, RT=room
temperature, MPLC=intermediate pressure liquid chromatography
THF=tetrahydrofuran, DMF=dimethylformamide, abs.=absolute,
CDI=carbonyldiimidazole,
EDC=N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride,
HOBT=1-hydroxybenzotriazole, TEA=triethylamine.
.sup.1 H-NMR-Spectrum=proton resonance spectrum, taken at 100 MHz.
The chemical shifts are given in ppm against TMS as a standard
(.delta.=0.0), whereby s=singlet, d=doublet, t=triplet,
dt=doublet-triplet, m=multiplet, ar=aromatic, py=pyridine.
Example 1
N-[4-(4-Phenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide
(Substance 52)
7.2 g (48.5 mmol) 3-(3-pyridyl)-acrylic acid are suspended in 80 ml
absolute dichloromethane and after addition of two drops pyridine,
are cooled to ca. 0.degree. C. in an ice bath under moisture
exclusion. 12 ml (132 mmol) of oxalyl chloride are slowly added and
the mixture is first stirred for 30 min under ice cooling and then
stirred overnight at RT. Subsequently, the solvent and excess
oxalyl chloride are distilled off on a rotary evaporator. In order
to completely remove the oxalyl chloride, the colorless residue as
dried further for two hours under high-vacuum. The acid chloride
obtained in this manner is suspended without further purification
in 50 ml absolute dichloromethane and cooled to ca. 0.degree. C. in
an ice bath under moisture exclusion. 10.25 g (44.1 mmol) are
dissolved in 50 ml absolute dichloromethane and are added dropwise
to this suspension. After complete addition, the ice bath is
removed and the reaction is stirred for a further two hours at RT.
The mixture is subsequently concentrated, taken up in 10% sodium
hydroxide solution and extracted three times each with
dichloromethane. The combined organic phases are washed with 20 ml
water, dried, over sodium sulfate and the solvent is removed under
vacuum. The residue is chromatographically purified over silica gel
with CHCl.sub.3 /CH.sub.3 OH (97/3 to 90/10) and crystallized first
from 40 ml acetonitrile and subsequently from 25 ml from acetic
ethyl acid ester after evaporation of the solvent: Colorless
crystals with a MP. of 118-119.degree. C.; yield 1.9 g (12%).
C.sub.23 H.sub.29 N.sub.3 O (363.5).
IR-Spectrum (KBr): .nu.(NH) 3280 cm.sup.-1 .nu.(C.dbd.O) 1650, 1550
cm.sup.-1 .nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.45-2.75 (13H, m, C--CH.sub.2 --CH.sub.2 --C,
piperidine, N--CH.sub.2) 2.95-3.20 (2H, m, piperidine) 3.25-3.60
(2H, m, CONHCH.sub.2) 6.50 (1H, d, CH.dbd.CHCO, J = 15.7 Hz)
6.85-7.15 (1H, m, NH) 7.05-7.40 (6H, m, Ar, Py) 7.63 (1H, d,
CH.dbd.CHCO, J = 15.7 Hz) 7.70-7.80 (1H, m, Py) 8.45-8.60 (1H, m,
Py) 8.65-8.80 (1H, m, Py)
Example 2
N-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-3-pyridin-3-yl-acrylamide
(Substance 54)
Production analogous to Example 1.
Batch size: 6.3 g (42.5 mmol) 3-(3-pyridyl)-acrylic acid, 11 ml
(127 mmol) oxalyl chloride and 10.5 g (38.7 mmol)
4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butylamine.
In the purification, chromatography first occurs with CHCl.sub.3
/CH.sub.3 OH/NH.sub.4 OH (95/5/0 to 90/10/1); subsequently,
crystallization occurs twice each from 40 ml methanol: Colorless
crystals with an MP. 169-171.degree. C.; yield 1.35 g
C.sub.25 H.sub.30 N.sub.4 O (402.5).
IR-Spectrum (KBr): .nu.(NH) 3250 cm.sup.-1 .nu.(C.dbd.O) 1660, 1540
cm.sup.-1 .nu.(C.dbd.C) 1630 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.40-2.60 (12H, m, C--CH.sub.2 --CH.sub.2 --C,
piperidine, N--CH.sub.2) 2.70-3.25 (3H, m, piperidine) 3.25-3.60
(2H, m, CONHCH.sub.2) 6.48 (1H, d, CH.dbd.CHCO, J = 15.6 Hz)
6.80-7.45 (6H, m, Ar, Py, NH) 7.45-7.80 (3H, m, CH.dbd.CHCO, Ar,
Py) 7.95-8.20 (1H, m, NH) 8.40-8.60 (1H, m, Py) 8.60-8.80 (1H, m,
Py)
Example 3
N-{4-[4-(2-oxo-2,3-Dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-3-pyr
idin-3-yl-acrylamide (Substance 55)
Production analogous to Example 1.
Batch size: 1.47 g (9.9 mmol) 3-(3-pyridyl)-acrylic acid, 1.15 ml
(13.5 mmol) oxalyl chloride and 2.6 g (9.0 mmol)
4-[4-(2-oxo-2.3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butylamine.
In the purification, chroratography first occurs from 25 ml
acetonitrile; subsequently, chromatography occurs with CHCl.sub.3
/CH.sub.3 OH (90/10): Yield 0.2 g (5%) in the form of a colorless
foam.
C.sub.24 H.sub.29 N.sub.5 O.sub.2 (419.5).
IR-Spectrum (KBr): .nu.(NH) 3250 cm.sup.-1 .nu.(C.dbd.O) 1650, 1540
cm.sup.-1 .nu.(C.dbd.C) 1615 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.50-2.80 (12H, m, C--CH.sub.2 --CH.sub.2 --C,
piperidine, N--CH.sub.2) 3.00-3.30 (2H, m, piperidine) 3.30-3.60
(2H, m, CONHCH.sub.2) 4.31-4.60 (1H, m, piperidine) 6.40-6.65 (1H,
m, NH) 6.53 (1H, d, CH.dbd.CHCO, J = 15.6 Hz) 6.90-7.45 (5H, m, Ar,
Py) 7.65 (1H, d, CH.dbd.CHCO, J = 15.6 Hz) 7.70-7.90 (1H, m, Py)
8.45-8.60 (1H, m, Py) 8.70-8.85 (1H, m, Py) 9.00-9.15 (1H, bs,
NH)
Example 4
N-[4-(4-Benzotriazol-1-yl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide
(Substance 60)
Production analogous to Example 1.
Batch size: 3.1 g (22.5 mmol) 3-(3-pyridyl)-acrylic acid, 5.4 ml
(45 mmol) oxalyl chloride and 5.6 g (20.5 mmol)
4-(4-benzotriazol-1-yl-piperidin-1-yl)-butylamine.
In the purification, chromatography first occurs with CHCl.sub.3
/CH.sub.3 OH (98/2 to 90/10), subsequently, crystallization occurs
twice each from 200 ml cholorobutane and 400 ml
isopropanol/diisopropylether (1/3): Colorless crystals with an MP.
127-129.degree. C.; Yield 1.0 g (12%).
C.sub.23 H.sub.28 N.sub.6 O (404.5).
IR-Spectrum (KBr): .nu.(NH) 3260 cm.sup.-1 .nu.(C.dbd.O) 1660, 1540
cm.sup.-1 .nu.(C.dbd.C) 1625 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.40-2.00 (4H, m, C--CH.sub.2 --CH.sub.2 --C)
2.00-2.80 (8H, m, piperidine, N- CH.sub.2) 3.00-3.35 (2H, m,
piperidine) 3.35-3.65 (2H, m, CONHCH.sub.2) 4.55-4.95 (1H, m,
piperidine) 6.25-6.60 (1H, m, NH) 6.52 (1H, d, CH.dbd.CHCO, J =
15.7 Hz) 7.20-8.20 (7H, m, CH.dbd.CHCO, Ar, Py) 8.50-8.70 (1H, m,
Py) 8.70-8.90 (1H, m, Py)
Example 5
N-{4-[4-(Hydroxy-diphenylmethyl)-piperidin-1-yl]-butyl}-2-(pyridin-3-yloxy)
-acetamide (Substance 36)
1.8 g (11.6 mmol) (pyridin-3-yloxy)-acetic acid and 1.7 ml (12.2
mmol) TEA are suspended in 80 ml absolute dichlormethane and cooled
to ca. 0.degree. C. under moisture exclusion. 2.1 g (13.7 mmol) 88%
HOBT and 2.7 g (14.1 mmol) EDC are added and the mixture is stirred
for 30 min under ice-cooling. 4,. g (13.0 mmol)
4-[4-(hydroxy-diphenylmehyl)-piperidin-1-yl]-butylamine are added
and the mixture is stirred overnight without cooling. Subsequently,
the batch is washed with 50 ml 1M sodium hydroxide solution and
twice each with 30 ml water. The organic phase is dried over sodium
sulfate and the solvent is removed under vacuum. The residue is
chromatographically purified over silica gel with CHCl.sub.3
/CH.sub.3 OH/NH.sub.4 OH (90/10/0 to 90/10/1): Yield 2.0 g (34%) of
a colorless resin.
C.sub.29 H.sub.35 N.sub.3 O.sub.3 (473.6)
IR-Spectrum (KBr): .nu.(NH) 3300 cm.sup.-1 .nu.(C.dbd.O) 1660, 1540
cm.sup.-1 .sup.1 H-NMR-Spectrum (CDCl.sub.3): 1.20-3.60 (18H, m,
C--CH.sub.2 --CH.sub.2 --C, N--CH.sub.2, OH, CONHCH.sub.2,
piperidine) 4.49 (2H, s, CO--CH.sub.2) 6.70-7.05 (1H, m, NH)
7.00-7.80 (12H, m, Ar, Py) 8.20-8.50 (2H, m, Py)
Example 6
N-[4-(4,4-Diphenyl-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acrylamide
(Substance 82)
2.4 g (16.0 mmol) 3-(3-pyridyl)-acrylic acid and 2.9 g (17.6 mmol)
CDI are heated under reflux in 150 ml absolute THF under moisture
exclusion. After an hour, this is cooled to RT and 6.0 g (19.2
mmol) 4-(4,4-diphenyl-piperidin-1-yl)-butylamine, dissolved in 25
ml absolute THF, are added dropwise. After addition, this is
stirred for a further three hours at RT and left to stand
overnight. The mixture is poured into 200 ml water and extracted
three times each with 100 ml acetic acid ethyl ester by shaking.
The combined organic phases are washed with saturated
NaCl-solution, dried over sodium sulfate and the solvent is removed
under vacuum. The residue is chromatographically pre-purified over
silica gel with CHCl.sub.3 /CH.sub.3 OH (95/5). After removal of
the solvent, crystallization occurs from 130 ml isopropanol:
Colorless crystals with MP. 207-208.degree. C.: Yield 2.0 g
(28%).
C.sub.29 H.sub.33 N.sub.3 O (439.6).
IR-Spectrum (KBr): .nu.(NH) 3260 cm.sup.-1 .nu.(C.dbd.O) 1650, 1550
cm.sup.-1 .nu.(C.dbd.C) 1610 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.50-1.75 (4H, m, C--CH.sub.2 --CH.sub.2 --C)
2.20-2.70 (10H, m, piperidine, N- CH.sub.2) 3.25-3.55 (2H, m,
CONHCH.sub.2) 6.46 (1H, d, CH.dbd.CHCO, J = 15.7 Hz) 7.00-7.35
(12H, m, Ar, Py) 7.60 (1H, d, CH.dbd.CHCO, J = 15.7 Hz) 7.60-7.75
(1H, m, Py) 8.45-8.60 (1H, m, Py) 8.60-8.75 (1H, m, Py)
Example 7
N-{4-[4-(6,11-Dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butyl}
-3-pyridin-3-yl-propionamid.-dihydrochlorid.semi-isopropanol
(Substance 110 as a dihydrochloride)
Production analogous to Example 6.
Batch size: 1.4 g (9.3 mmol) 3-(3-pyridyl)-propionic acid, 1.6 (9.9
mmol) CDI and 3.0 g (8.2 mmol)
4-[4-(6,11-dihydro-dibenzo-[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylam
ine.
In the purification, this is chromatographically purified over
silica gel with CHCl.sub.3 /CH.sub.3 OH/NH.sub.4 OH (95/5/0.5).
After removal of the solvent, the residue is dissolved in 35 ml
isopropanol and mixed with 3 ml 6.5M isopropanolic HCl-solution and
rotated in: amorphic solid with MP. 123-135.degree. C.: Yield 2.6 g
(53%).
C.sub.31 H.sub.35 N.sub.3 OS.2HCl.1/2C.sub.3 H.sub.6 O (600.7).
IR-Spectrum (KBr): .nu.(NH) 3400 cm.sup.-1 .nu.(C.dbd.O) 1640, 1545
cm.sup.-1 .sup.1 H-NMR-Spectrum (CD.sub.3 OD): 1.35-2.00 (4H, m,
C--CH.sub.2 --CH.sub.2 --C) 2.30-3.75 (18H, m, piperidine,
N--CH.sub.2, CONHCH.sub.2, S--CH.sub.2, CO--CH.sub.2, Py-CH.sub.2)
6.95-7.45 (8H, m, Ar) 7.90-8.10 (1H, m, Py) 8.45-8.65 (1H, m, Py)
8.65-8.85 (2H, m, Py)
Example 8
N-{4-[4-(6,11-Dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl}-butyl]
-5-pyridin-3-yl-pentanamide (Substance 112)
Production analogous to Example 6.
Batch size: 1.6 g (9.0 mmol) 5-(3-pyridyl)-pentanic acid, 1.6 g
(9.9 mmol) CDI and 3.0 g (8.2 mmol)
4-[4-(6,11-dihydro-dibenzo-[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylam
ine.
In the purification, this is chromatographically purified over
silica gel with CHCl.sub.3 /CH.sub.3 OH/NH.sub.4 OH (97/3/0,3):
Yield 2.4 g (55%) of a light brown resin.
C.sub.33 H.sub.35 N.sub.3 OS (525.8).
IR-Spectrum (KBr): .nu.(NH) 3270 cm.sup.-1 .nu.(C.dbd.O) 1640, 1545
cm.sup.-1 .sup.1 H-NMR-Spectrum (CDCl.sub.3): 1.40-1.80 (8H, m,
C--CH.sub.2 --CH.sub.2 --C) 2.00-2.80 (14H, m, piperidine,
N--CH.sub.2, CO--CH.sub.2, Py-CH.sub.2) 3.10-3.40 (2H, m,
CONHCH.sub.2) 3.39 (1H, d, S--CH.sub.2, J = 13.3 Hz) 4.92 (1H, d,
S--CH.sub.2, J = 13.3 Hz) 6.05-6.30 (1H, m, NH) 6.90-7.35 (9H, m,
Ar, Py) 7.40-7.60 (1H, m, Py) 8.30-8.55 (2H, m, Py)
Example 9
N-{4-[4-(4,9-Dihydro-thieno[2,3-b]benzo[e]thiepin-4-yliden)-piperidin-1-yl]
-butyl}-3-pyridin-3-yl-propionamide (Substance 117)
Production analogous to Example 6.
Batch size: 1.4 g (9.0 mmol) 3-(3-pyridyl)-propionic acid, 1.6 g
(9.9 mmol) CDI and 4.0 g (10.8 mmol)
4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]-thiepin-4-yliden)-piperidin-1-yl]
butylamine.
In the purification, chromatography occurs over silica gel with
CHCl.sub.3 /CH.sub.3 OH (95/5 to 90/10); subsequently, this is
crystallized from 25 ml acetonitrile: Colorless crystals with MP.
80-81.degree. C.: Yield 2.9 g (64%).
C.sub.29 H.sub.33 N.sub.3 OS.sub.2 (503.7).
IR-Spectrum (KBr): .nu.(NH) 3300 cm.sup.-1 .nu.(C.dbd.O) 1670, 1535
cm.sup.-1 .sup.1 H-NMR-Spectrum (CDCl.sub.3): 1.25-1.70 (4H, m,
C--CH.sub.2 --CH.sub.2 --C) 1.90-2.85 (12H, m, piperidine,
N--CH.sub.2, CO--CH.sub.2) 2.85-3.10 (2H, m, Py-CH.sub.2) 3.10-3.40
(2H, m, CONHCH.sub.2) 3.52 (1H, d, S--CH.sub.2, J = 13.3 Hz) 4.91
(1H, d, S--CH.sub.2, J = 13.3 Hz) 6.10-6.40 (1H, m, NH) 6.72 (1H,
d, Ar, J = 5.2 Hz) 7.02 (1H, d, Ar, J = 5.2 Hz) 6.95-7.45 (5H, m,
Ar, Py) 7.45-7.70 (1H, m, Py) 8.40-8.60 (2H, m, Py)
Example 10
N-{4-[4-(4,9-Dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-yl
])-butyl)}-3-pyridin-3-yl-acrylamide (Substance 118)
Production analogous to Example 6.
Batch size: 1.3 g (9.0 mmol) 3-(3-pyridyl)-acrylic acid, 1.6 g (9.9
mmol) CDI and 4.0 g (10.8 mmol)
4-[4-(4,9-dihydrothieno[2,3-b]-benzo
[e]thiepin-4-yliden)-piperidin-1-yl]-butylamine.
In the purification, flash-chromatography is carried out twice with
CHCl.sub.3 /CH.sub.3 OH (100/0 to 95/5 and 100/0 to 98/2);
subsequently, this is crystallized from 20 ml acetic acid ethyl
ester: Colorless crystals pith an MP. 131-135.degree. C.; Yield 0.9
g (20%).
C.sub.29 H.sub.31 N.sub.3 OS.sub.2 (501.7).
IR-Spectrum (KBr): .nu.(NH) 3300 cm.sup.-1 .nu.(C.dbd.O) 1655, 1545
cm.sup.-1 .nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.40-1.80 (4H, m, C--CH.sub.2 --CH.sub.2 --C)
1.90-3.00 (10H, m, piperidine, N- CH.sub.2) 3.25-3.55 (2H, m,
CONHCH.sub.2) 3.52 (1H, d, S--CH.sub.2, J = 13.4 Hz) 4.90 (1H, d,
S--CH.sub.2, J = 13.4 Hz) 6.49 (1H, d, CH.dbd.CHCO, J = 15.7 Hz)
6.60-6.85 (1H, m, NH) 6.72 (1H, d, Ar, J = 5.2 Hz) 6.95-7.15 (1H,
m, Py) 7.02 (1H, d, Ar, J = 5.2 Hz) 7.15-7.45 (4H, m, Ar) 7.62 (1H,
d, CH.dbd.CHCO, J = 15.7 Hz) 7.70-7.90 (1H, m, Py) 8.45-8.60 (1H,
m, Py) 8.65-8.80 (1H, m, Py)
Example 11
N-[4-(4-Diphenylphosphinoyloxy-piperidin-1-yl)-butyl]-3-pyridin-3-yl-acryla
mide (Substance 188)
Production analogous to Example 1.
Batch size: 2.15 g (14.4 mmol) 3-(3-pyridyl)-acrylic acid, 4 ml (39
mmol) oxalyl chloride and 4.9 g (13.1 mmol)
4-(4-diphenyl-phosphinoyloxy-piperidin-1-yl)-butylamine.
In the purification, chromatography first occurs with CHCl.sub.3
/CH.sub.3 OH/NH.sub.4 OH (90/10/1); subsequently, crystallization
occurs from diisopropylether: Colorless crystals with an MP.
151-153.degree. C.: Yield 3.9 g (63%).
C.sub.29 H.sub.34 N.sub.3 O.sub.3 P (503.6).
IR-Spectrum (KBr): .nu.(NH) 3270 cm.sup.-1 .nu.(C.dbd.O) 1665, 1540
cm.sup.-1 .nu.(C.dbd.C) 1625 cm.sup.-1 .sup.1 H-NMR-Spectrum
(CDCl.sub.3): 1.40-1.80 (4H, m, C--CH.sub.2 --CH.sub.2 --C)
1.80-2.90 (10H, m, piperidine, N- CH.sub.2) 3.20-3.55 (2H, m,
CONHCH.sub.2) 4.30-4.65 (1H, m, piperidine) 6.50 (1H, d,
CH.dbd.CHCO, J = 15.7 Hz) 6.70-7.00 (1H, m, NH) 7.15-8.00 (13H, m,
Ar, Py, CH.dbd.CHCO) 8.45-8.65 (1H, m, Py) 8.65-8.80 (1H, m,
Py)
Example 12
N-[4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-3-pyridin-3-yl-acrylamide
(Substance 92)
Production analogous to Example 6.
Batch size: 4.0 g (26.8 mmol) 3-(3-pyridyl)-acrylic acid, 5.7 g
(35.2 mmol) CDI and 6.4 g (29.9 mmol)
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-butylamine.
In the purification, chromatography occurs twice over silica gel
with CHCl.sub.3 /CH.sub.3 OH/NH.sub.4 OH (95/5/0 to 91/9/0 and
90/9/0,5): Yield 0.3 g (3%) as colorless resin.
C.sub.19 H.sub.27 N.sub.3 O.sub.3 (345.4).
IR-Spectrum (CH.sub.2 Cl.sub.2): .nu.(NH) 3320 cm.sup.-1
.nu.(C.dbd.O) 1680, 1560 cm.sup.-1 .nu.(C.dbd.C) 1640 cm.sup.-1
.sup.1 H-NMR-Spectrum (CDCl.sub.3): 1.40-1.95 (8H, m, C--CH.sub.2
--CH.sub.2 --C, piperidine) 2.20-2.90 (6H, m, piperidine, N-
CH.sub.2) 3.20-3.55 (2H, m, CONHCH.sub.2) 3.96 (4H, s, O--CH.sub.2
--CH.sub.2 --O) 6.49 (1H, d, CH.dbd.CHCO, J = 15.7 Hz) 6.90-7.15
(1H, m, NH) 7.20-7.40 (1H, m, Py) 7.61 (1H, d, CH.dbd.CHCO, J =
15.7 Hz) 7.70-7.90 (1H, m, Py) 8.50-8.65 (1H, m, Py) 8.65-8.80 (1H,
m, Py)
PRODUCTION OF THE STARTING SUBSTANCES
Example A
4-(4-Phenyl-piperidin-1-yl)-butylamine
a) 2-[4-(4-Phenyl-piperidin-1-yl)-butyl]-isoindolin-1,3-dione:
b)
10.0 g (62.4 mmol) 4-phenylpiperidine, 18.0 g (62.4 mmol)
N-(4-bromobutyl)-phthalimide and 17.3 g (125 mmol) potassium
carbonate are suspended in 100 ml DMF and stirred for three hours
at 60.degree. C. After cooling, the mixture is concentrated under
vacuum and the residue is distributed between chloroform and water.
The organic phase is dried over sodium sulfate and steam evaporated
under vacuum until dry. The residue is chormatographically purified
over silica gel with CHCl.sub.3 /CH.sub.3 OH (95/5): Yield 20.7
g.
b) 4-(4-Phenyl-piperidin-1-yl)-butylamine:
c)
20 g (61.2 mmol)
2-[4-(4-phenyl-piperidin-1-yl)-butyl]-isoin-dolin-1,3-dione and 6.1
g (122.5 mmol) hydrazine hydrate are heated under reflux in 250 ml
ethanol for 3 hours. The cooled solution is concentrated under
vacuum and the residue is taken up in chloroform. The suspension is
filtered and the residue is distributed between chloroform and 10%
sodium hydroxide solution. The combined organic phases are dried
over sodium sulfate and steam evaporated under vacuum until dry.
The resin is further processed without further purification: Yield
11.7 g (82%).
Example B
4-[4-(1H-Indol-3-yl)-piperidin-1-yl]-butylamine
a)
2-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-isoindolin-1,3-dione:
The reaction of the piperidine with the phthalimide occurs
analogously to Example A)a).
Batch size: 20 g (99.9 mmol) 4-(3-indoylpiperidine), 29.6 (104.9
mmol) N-(4-bromobutyl)-phthalimide and 20.3 g (149.8 mmol)
potassium carbonate in 250 ml DMF.
Purification occurs by chromatography over silica gel with
CHCl.sub.3 /CH.sub.3 OH (98/2 to 95/5): Yield 33.8 g (84%).
b) 4-[4-(1H-Indol-3-yl)-piperidin-1-yl]-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 23.5 g (58.5 mmol)
2-{4-[4-(1H-indol-3-yl)-piperi-din-1-yl]-butyl}-isoindolin-1,3-dione
and 6.0 ml (117 mmol) hydrazine.hydrate in 150 ml ethanol.
In the work-up, acetic acid ethyl ester is used instead of
chloroform. The accumulated crude product is further processed
without further purification: Yield 10.5 g (66%).
Example C
4-[4-(2-oxo-2,3-Dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butylamine
a)
2-{4-[4-(2-oxo-2,3-Dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-isoi
ndolin-1,3-dione:
Reaction of the piperidine with the phthalimide occurs analogously
to Example A)a).
Batch size: 15.0 g (69 mmol)
4-(2-oxo-2,3-dihydrobenzoimid-azol-1-yl)-piperidine, 19.4 (69 mmol)
N-(4-bromobutyl)-phthalimide and 19.0 g (138 mmol) potassium
carbonate in 220 ml DMF.
The mixture is stirred at RT for 24 hours. The purification occurs
by chromatography over silica gel with CHCl.sub.3 /CH.sub.3 OH
(95/5): Yield 11.8 g (40%).
b)
4-[4-(2-oxo-2,3-Dihydro-benzoimidazo-1-yl)-piper4din-1-yl]-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 11.5 g (27.4 mmol)
2-{4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butyl}-isoi
ndolin-1,3-dione and 2.7 ml (55 mmol) hydrazine.hydrate in 60 ml
ethanol. The accumulated crude product is further processed without
further purification: Yield 5.1 g (64%).
Example D
4-(4-Benzotriazol-1-yl-piperidin-1-yl)-butylamine
a)
2-[4-(4-Benzotriazol-1-yl-piperidin-1-yl)-butyl]-isoindolin-1,3-dione:
Reaction of the phthalimide to the amine occurs analogously to
Example A)a).
Batch 10.0 g (49.4 mmol 4-(4-benzotriazol-1-yl)-piperidine, 13.9
(490.4 mmol) N-(4-bromobutyl)-phthalimide and 19.0 g (144.7 mmol)
potassium carbonate in 120 ml DMF.
The purification occurs by chromatography over silica gel with
CHCl.sub.3 /CH.sub.3 OH (98/2): Yield 16.3 g (88%).
b) 4-(4-Benzotriazol-1-yl-piperidin-1-yl)-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 16.3 g (42.7 mmol)
2-[4-(4-benzotriazol-1-yl-pi-peridin-1-yl)-butyl]-isoindolin-1,3-dione
and 4.8 ml (98 mmol) hydrazine.hydrate in 130 ml ethanol.
In the work-up, acetic acid ethyl ester is used instead of
chloroform. Purification occurs by chromatography over silica gel
with CHCl.sub.3 /CH.sub.3 OH/NH.sub.4 OH (90/10/0 to 80/20/2):
Yield 5.6 g (47%).
Example E
4-[4-(Hydroxy-diphenylmethyl)-piperidin-1-yl]-butylamine
a)
2-(-[4-(Hydroxy-diphenylmethyl)-piperidin-1-yl]-butyl)-isoindolin-1,3-dion
e:
Reaction of the piperidine with the phthalimide occurs analogously
to Example A)a).
Batch size: 50.0 g (187 mmol)
4-(diphenyl-hydroxymethyl)-pi-peridine, 58.0 (206 mmol)
N-(4-bromobutyl)-phthalimide and 31.0 g (224 mmol) potassium
carbonate in 250 ml DMF.
Purification occurs by a crystallization from 200 ml acetic acid
ethyl ester. Colorless crystals with MP. 148-150.degree. C. Yield
65.0 g (74%).
b) 4-[4-(Hydroxy-diphenylmethyl)-piperidin-1-yl]-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 60.0 g (128 mmol)
2-{4-[4-(hydroxy-diphenyl-methyl)-piperidin-1-yl]-butyl}-isoindolin-1,3-di
one and 12.8 g (256 mmol) hydrazine.hydrate in 300 ml ethanol.
In the work-up, toluene at 50.degree. C. is used instead of
chloroform. The organic phase is cooled and the resulting
precipitate is filtered off. Colorless crystals with an MP.
90.degree. C.: Yield 36.0 g (83%).
Example F
4-(4,4-Diphenyl-piperidin-1-yl)-butylamine
a)
2-[4-(4,4-Diphenyl-piperidin-1-yl)-butyl]-isoindolin-1,3-dione:
30.0 a (124 mmol) 4,4-Diphenylpiperidine, 35.2 g (124 mmol)
N-(4-bromobutyl)-phthalimide, 25.9 g (186 mmol) potassium carbonate
and 25.8 g (170 mmol) sodium iodide are suspended in 500 mmol ethyl
methyl ketone and heated to boiling for five hours. Alter cooling,
the solvent is distilled off and the residue is distributed between
chloroform and water. The organic phase is dried over sodium
sulfate and steam evaporated under vacuum until dry. The residue is
crystallized from 100 ml acetonitrile. Colorless crystals with a
MP. 123-125.degree. C.: Yield 42.0 g (75%).
b) 4-(4,4-Diphenyl-piperidin-1-yl)-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 40.0 g (90.3 mmol)
2-[4-(4,4-diphenyl-piperidin-1-yl)-butyl]-isoindolin-1,3-dione and
8.8 ml (180.6 mmol) hydrazine.hydrate in 400 ml ethanol.
In the work-up, dichloromethane is used instead of chloroform. The
accumulated crude product is further processed without further
purification: Yield 17.3 g (62%).
Example G
4-[4-(6,11-Dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylamin
e
a)
2-{4-[4-(6,11-Dihydro-dibenzo[b,e]thiepin-11-yliden)-piperi-din-1-yl]-buty
l}-isoindolin-1,3-dione.hydrochloride:
The reaction of the piperidine with the phthalimide occurs
analogously to Example A)a).
Batch size: 20.0 g (60.6 mmol)
4-(6,11-dihydro-dibenzo[b,e]-thiepin-1-yliden)-piperidine.hydrochloride,
19.0 (66 mmol) N-(4-bromobutyl)-phthalimide and 25.0 g (180 mmol)
potassium carbonate in 150 ml DMF.
The reaction occurs overnight without heating.
In the purification, the residue is dissolved in 300 ml methanol
and mixed with 20 ml 6.5M isopropanolic hydrochloric acid. The salt
precipitating in the cold is drawn off and dried: Yield 39.6 g
(78%).
b)
4-[4-(6,11-Dihydro-dibenzo[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylami
ne:
The reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 3.0 g (56.4 mmol)
2-{4-[4-(6,11-dihydro-dibenzo-[b,e]thiepin-11-yliden)-piperidin-1-yl]-buty
l}-isoindolin-1,3-dione hydrochloride and 5.7 ml (120 mmol)
hydrazine.hydrate in 300 ml ethanol.
In the work-up, toluene is used chloroform. The accumulated crude
product is further processed without further purification: Yield
20.2 g (81%).
Example H
4-[4-(4,9-Dihydro-thieno[2,3-b]-benzo[b,e]thiepin-4-yliden)-piperidin-1-yl]
-butylamine
a)
2-{4-[4-(4,9-Dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidin-1-y
l]-butyl}-isoindolin-1,3-dione:
The reaction of the piperidine with the phthalimide occurs
analogously to Example A)a).
Batch size: 40.0 g (119.1 mmol)
4-(4,9-dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden)-piperidine.
hydrochloride, 35.6 (123.8 mmol) N-(4-bromobutyl)-phthalimide and
49.2 g (357.2 mmol) potassium carbonate in 400 ml DMF.
The reaction occurs overnight at RT.
In the work-up acetic acid ethyl ester is used instead of
chloroform. In the purification, the residue is crystallized from
400 mmol dioxane/water (10/1): Yield 39.0 g (65%).
b)
4-[4-(4,9-Dihydro-thieno[2,3-b]-benzo[e]thiepin-4-yliden-piper-din-1-yl]-b
utylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 47.0 g (93.9 9mmol)
2-[4-[4-(4,9-dihydro-thieno[2,3-b]-benzo
[e]thiepin-4-yliden)-piperidin-1-yl]-butyl]-isoindolin-1,3-dione
and 9.0 ml (187.7 mmol) hydrazine.hydrate in 470 ml ethanol.
In the work-up, toluene is used instead of chloroform. The
accumulated crude product is further processed without further
purification: Yield 38.0 g.
Example I
4-(4-Diphenylphosphinoyloxypiperidin-1-yl)-butylamine
a) 2-[4-(4-Hydroxypiperidin-1-yl)-butyl]-isoindolin-1,3-dione:
The reaction of the piperidine with the phthalimide occurs
analogously to Example A)a) under addition of sodium iodide.
Batch size: 15.0 g (146.3 mmol) 4-hydroxypiperidine, 41.8 (148.3
mmol) N-(4-bromobutyl)-phthalimide, 41.0 g (296.6 mmol) potassium
carbonate and 4.5 g (30 mmol) sodium iodide in 300 ml DMF.
The accumulated crude product is further without further
purification: Yield 33.2 g (74%).
b)
2-[4-(4-Diphenylphosphinoyloxy-piperidin-1-yl)-butyl]-isoindolin-1,3-dione
:
20.0 g (66.1 mmol)
2-[4-(4-hydroxypiperidin-1-yl)-butyl]-isoindolin-1,3-dione and 9.2
ml (66.1 mmol) TEA are dissolved in 100 ml absolute dichloromethane
and cooled to ca. 0.degree. C. under moisture exclusion. 13.0 ml
diphenylphosphinic chloride are added dropwise and the mixture is
heated at RT for two hours. Subsequently, the batch is washed twice
with water. The organic phase is dried over sodium sulfate and the
solvent is removed under vacuum. The accumulated crude product is
further processed without purification: Yield 32.0 g (96%).
c) 4-(4-Diphenylphosphinoyloxypiperidin-1-yl)-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
Example A)b).
Batch size: 25.0 g (49.7 mmol)
2-[4-(4-diphenylphosphinoyloxy-piperidin-1-yl]-butyl-isoindolin-1,3-dione
and 5.0 g (99.5 mmol) hydrazine.hydrate in 200 ml ethanol.
In the work-up, acetic acid ethyl ester is used instead of
chloroform. The accumulated crude product is further processed
without purification: Yield 13.0 g (70%).
Example J
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-butylamine
2-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-isoindolin-1,3-dione:
The reaction of the piperidine with the phthalimide occurs
analogously to Example A)a).
Batch size: 9.4 g (65.6 mmol) piperidon-4-ethylenketal-18,5 g (65.6
mmol) N-(4-bromobutyl)-phthalimide and 20.0 g (144 mmol) potassium
carbonate in 200 ml ethyl methyl ketone.
The reaction mixture is heated under reflux for 6 hours. The
purification occurs by chromatography over silica gel with.
CHCl.sub.3 /CH.sub.3 OH (97/3): Yield 22.0 g (97%).
b) 4-(1,4-Dioxa-8-azaspiro[4.5]dec-6-yl)-butylamine:
Reaction of the phthalimide to the amine occurs analogously to
example A)b).
Batch size: 21.9 g (63.6 mmol)
2-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-isoindolin-1,3-dione
and 6.2 ml (127 mmol) hydrazine.hydrate in 200 ml ethanol.
In the work-up, the acetic acid ethyl ester is used instead of
chloroform. The accumulated crude product is further processed
without further purification: Yield 6.4 g (47%).
The active ingredients according to the invention can be processed
to the desired medicaments in the form of their acid addition
salts, hydrates or solvates individually or in combination with
each other, optionally under addition of other active ingredients.
In the case of the combination of active ingredients according to
the invention with other medicinals, these can also optionally be
separately present next to each other in the medicine packaging,
for example as tablets next to vials, depending on the
requirements.
Further subject-matter of the invention is a method for the
treatment of the human or animal body in which a compound or
compound mixture according to formula (I), wherein the substituents
have the above described meanings, is administered for treatment of
tumors and/or as a cytostatic agent, cancerostatic agent or as an
immunosuppressing agent, optionally in combination with further
cytostatic or immunosuppressive active ingredients or other active
ingredients suitable for the named indications.
Furthermore, the invention relates to a compound or compound
mixture according to formula (I) for use in a diagnostic
therapeutic method in which the therapeutic use is carried out in
connection with one or more medical indications with tumors or for
immunosuppression, optimally in combination with further
pharmaceuticals suitable for the named indications.
The use of one or more compounds according to formula (I) for the
production of diagnostic agents or medicaments for the treatment t
he human or animal body, especially in connection with one or more
medical indications in the treatment of tumors or for
immunosuppression, optimally in combination with further
pharmaceuticals suitable in these indications or the use of
compounds according to formula (I) in a corresponding diagnosis
method also represent an embodiment according to the invention,
whereby the compounds for the designated medical indications are
included that are excluded from the product claims in view of the
definition of group G. The medical indications according to the
invention of the compounds excluded from the protective scope of
the compound claims are new.
The respective suitable tumor indications are illustrated in the
last section of the description in the discussion of the
pharmacological test results.
A method for the production of medicaments with an amount of one or
more compounds according to formula (I) which are suitable for the
processing of these active ingredients together with respective
suitable pharmaceutically acceptable carriers and adjuvants for
finished medicinal forms equally belongs to the scope of protection
according to the invention.
Depending on the medical indication being considered, the
respective suitable medicinal form is selected for the suitable
therapeutic application. Thereby 0.001 or 0.01 to 2 mg and/or 0.1,
1, 2, 5, 10, 20, 25, 30, 50, 100, 200, 300, 500, 600, 800, 1000,
2000, 3000, 4000 or 5000 mg are considered as a single dosage
unit.
The invention also relates to the use of the compounds according to
formula (I) for treatment in the above indications, as well as a
diagnostic agent.
The production methods of the respective suitable medicaments as
well as a series of examples of medicinal forms and pharmacological
activities are described in the following for better understanding
of the invention. The following given examples as well as the above
synthesis examples serve for illustration of the claims without
limiting the protective scope. Skilled persons can correspondingly
modify the invention within the framework of their normal
capabilities without deviating from the protective scope.
Therapeutic Administration Forms
The production of medicaments with an amount Of one or more
compounds according to the invention and/or their use in the
application according to the invention occurs in the customary
manner by means of common pharmaceutical technology methods. For
this, the active ingredients as such or in the form of their salts
are processed together with suitable, pharmaceutically acceptable
adjuvants and carriers to medicinal forms suitable for the various
indications and types of application. Thereby, the medicaments can
be produced in such a manner that the respective desired release
rate is obtained, for example a quick flooding and/or a sustained
or depot effect.
Preparations for parenteral use, to which injections and infusions
belong, are among the most important systemically employed
medicaments for tumor treatment as well as for other
indications.
Preferably, injections are administered for the treatment of
tumors. These are prepared either in the form of vials or also as
so-called ready-to-use injection preparations, for example as
ready-to-use syringes or single use syringes in addition to
perforation bottles for multiple withdrawals. Administration of the
injection preparations can occur in the form of subcutaneous
(s.c.), intramuscular (i.m.), intravenous (i.v.) or intracutaneous
(i.c.) application. The respective suitable injection forms can
especially be produced as solutions, crystal suspensions,
nanoparticular or colloid-disperse systems, such as for example,
hydrosols.
The injectable formulations can also be produced as concentrates
which can be adjusted with aqueous isotonic dilution agents to the
desired active ingredient dosage. Furthermore, they can also be
produced as powders, such as for example lyophilisates, which are
then preferably dissolved or dispersed immediately before
application with suitable diluents. The infusions can also be
formulated in the form of isotonic solutions, fat emulsions,
liposome formulations, microemulsions and liquids based on mixed
micells, for example, based on phospholipids. As with injection
preparations, infusion formulations can also be prepared in the
form of concentrates to dilute. The injectable formulations can
also be applied in the form of continuous infusions as in
stationary as well as in out-patient therapy, for example in the
form of mini-pumps.
Albumin, plasma expanders, surface active compounds, organic
solvents, pH influencing compounds, complex forming compounds or
polymeric compounds can be added to the parenteral medicinal forms,
especially as substances for influencing the d adsorption of the
active ingredients to protein or polymers or also with the aim of
decreasing the adsorption of the active ingredient to materials
such as injection instruments or packaging materials, for example
plastic or glass.
The active ingredients can be bound to nanoparticles in the
preparations for parenteral use, for example on finely dispersed
particles based on poly(meth)acrylates, polyacetates,
polyglycolates, polyamino acids or polyether urethanes. The
parenteral formulations can also be constructively modified as
depot preparations, for example on the multiple unit principle,
where the active ingredients are incorporated in a most finely
distributed and/or dispersed, suspended form or as crystal
suspensions, or on the single unit principle, where the active
ingredient is enclosed in a medicinal form, for example, a tablet
or a seed which is subsequently implanted. Often, these
implantations or depot medicaments in single unit and multiple unit
medicinal forms consist of so-called biodegradable polymers, such
as for example, polyether urethanes of lactic and glycolic acid,
polyether urethanes, polyamino acids, poly(meth)acrylates or
polysaccharides.
Sterilized water, pH value influencing substances, such as for
example organic and inorganic acids or bases as well as their
salts, buffer substances for setting the pH value, agents for
isotonicity, such as for example sodium chloride, monosodium
carbonate, glucose and fructose, tensides and/or surface active
substances and emulsifiers, such as for example, partial fatty acid
esters of polyoxyethylene sorbitan (Tween.RTM.) or for example
fatty acid esters of polyoxethylene (Cremophor.RTM.), fatty oils
such as for example peanut oil, soybean oil and castor oil,
synthetic fatty acid esters, such as for example ethyl oleate,
isopropyl myristate and neutral oil (Miglyol.RTM.) as well as
polymer adjuvants such as for example gelatine, dextran,
polyvinylpyrrolidone, organic solvent additives which increase
solubility, such as for example propylene glycol, ethanol,
N,N-dimethylacetamide, propyene glycol or complex forming compounds
such as for example citrates and urea, preservatives, such as for
example hydroxypropyl benzoate and hydroxymethyl benzoate, benzyl
alcohol, anti-oxidants, such as for example sodium sulfate and
stabilizers, such as for example EDTA, are suitable as adjuvants
and carriers in the production of preparations for parenteral
use.
In suspensions, addition of thickening agents to prevent the
settling of the active ingredients from tensides and peptizers, to
secure the ability of the sediment to be shaken, or complex
formers, such as EDTA, ensues. This can also be achieved with the
various polymeric agent complexes, for example with polyethylene
glycols, polystyrol, carboxymethylcellulose, Pluronics.RTM. or
polyethylene glycol sorbitan fatty acid esters. The active
ingredient can also be incorporated in liquid formulations in the
form of inclusion compounds, for example with cyclodextrins. As
further adjuvants, dispersion agents are also suitable. For
production of lyophilisates, builders are also used, such as for
example mannite, dextran, saccharose, human albumin, lactose, PVP
or gelatine varieties.
As long as the active ingredients are not incorporated in the
liquid medicinal formulations in the form of a base, they are used
in the form of their acid addition salts, hydrates or solvates in
the preparations for parenteral use.
A further systemic application form of importance is peroral
administration as tablets, hard or soft gelatine capsules, coated
tablets, powders, pellets, microcapsules, oblong compressives,
granules, chewable tablets, lozenges, gums or sachets. These solid
peroral administration forms can also be prepared as sustained
action and/or depot systems. Among these are medicaments with an
amount of one or more micronized active ingredients, diffusions and
erosion forms based on matrices, for example by using fats,
wax-like and/or polymeric compounds, or so-called reservoir
systems. As a retarding agent and/or agent for controlled release,
film or matrix forming substances, such as for example
ethylcellulose, hydroxypropylmethylcellulose, poly(meth)acrylate
derivatives (for example Eudragit.RTM.),
hydroxypropylmethylcellulose phthalate are suitable in organic
solutions as well as in the form of aqueous dispersions. In this
connection, so-called bio-adhesive preparations are also to be
named in which the increased retention time in the body is achieved
by intensive contact with the mucus membranes of the body. An
example of a bio-adhesive polymer is the group of
Carbomers.RTM..
For sublingual application, compressives, such as for example
non-disintegrating tablets in oblong form of a suitable size with a
slow release of active ingredient, are especially suitable. For
purposes of a targeted release of active ingredients in the various
sections of the gastrointestinal tract, mixtures of pellets which
release at the various places are employable, for example mixtures
of gastric fluid soluble and small intestine soluble and/or gastric
fluid resistant and large intestine soluble pellets. The same goal
of releasing at various sections of the gastrointestinal tract can
also be conceived by suitably produced laminated tablets with a
core, whereby the coating of the agent is quickly released in
gastric fluid and the core of the agent is slowly released in the
small intestine milieu. The goal of controlled release at various
sections of the gastrointestinal tract can also be attained by
multilayer tablets. The pellet mixtures with differentially
released agent can be filled into hard gelatine capsules.
Anti-stick and lubricant and separating agents, dispersion agents
such as flame dispersed silicone dioxide, disintegrates such as
various starch types, PVC, cellulose esters as granulating or
retarding agents, such as for example wax-like and/or polymeric
compounds on the basis of Eudragit.RTM., cellulose or
Cremophor.RTM. are used as a further adjuvants for the production
of compressives, such as for example tablets or hard and soft
gelatine capsules as well as coated tablets and granulates.
Anti-oxidants, sweetening agents, such as for example saccharose,
xylite or mannite, masking flavors, aromatics, preservatives,
colorants, buffer substances, direct tableting agents, such as for
example microcrystalline cellulose, starch and starch hydrolysates
(for example Celutab.RTM.), lactose, polyethylene glycols,
polyvinylpyrrolidone and dicalcium phosphate, lubricants, fillers,
such as lactose or starch, binding agents in the form of lactose,
starch varieties, such as for example wheat or corn and/or rice
starch, cellulose derivatives, for example methylcellulose,
hydroxypropylcellulose or silica, talcum powder, stearates, such as
for example magnesium stearate, aluminium stearate, calcium
stearate, talc, siliconized talc, stearic acid, acetyl alcohol or
hydrated fats, etc. are also used.
In this connection, oral therapeutic systems constructed especially
on osmotic principles, such as for example GIT (gastrointestinal
therapeutic system) or OROS (oral osmotic system), are also to be
mentioned.
Effervescent tablets or tabsolute both of which represent
immediately drinkable instant medicinal forms which are quickly
dissolved or suspended in water are among the perorally
administrable compressives.
Among the perorally administrable forms are also solutions, for
example drops, juices and suspensions, which can be produced
according to the above given method, and can still contain
preservatives for increasing stability and optionally aromatics for
reasons of easier intake, and colorants for better differentiation
as well as antioxidants and/or vitamins and sweeteners such as
sugar or artificial sweetening agents. This is also true for
inspissated juices which are formulated with water before
ingestion. Ion exchange resins in combination with one or more
active ingredients are also to be mentioned for the production of
liquid injestable forms.
A special release form consists in the preparation of so-called
floating medicinal forms, for example based on tablets or pellets
which develop gas after contact with body fluids and therefore
float on the surface of the gastric fluid. Furthermore, so-called
electronically controlled release systems can also be formulated by
which active ingredient release can be selectively adjusted to
individual needs.
A further group of systemic administration and also optionally
topically effective medicinal forms are represented by rectally
applicable medicaments. Among these are suppositories and enema
formulations. The enema formulations can be prepared based on
tablets with aqueous solvents for producing this administration
form. Rectal capsules can also be made available based on gelatine
or other carriers.
Hardened fat, such as for example Witepsol.RTM., Massa
Estarinum.RTM., Novata.RTM., coconut fat, glycerol-gelatine masses,
glycerol-soap-gels and polyethylene glycols are suitable as
suppository bases.
For long-term application with a systematic active ingredient
release up to several weeks, pressed implants are suitable which
are preferably formulated on the basis of so-called biodegradable
polymers.
As a further important group of systemically active medicaments,
transdermal systems are also to be emphasized which distinguish
themselves, as with the above-mentioned rectal forms, by
circumventing the liver circulation system and/or liver metabolism.
These plasters can be especially prepared as transdermal systems
which are capable of releasing the active ingredient in a
controlled manner over longer or shorter time periods based on
different layers and/or mixtures of suitable adjuvants and
carriers. Aside from suitable adjuvants and carriers such as
solvents and polymeric components, for example based on
Eudragit.RTM., membrane infiltration increasing substances and/or
permeation promoters, such as for example oleic acid, Azone.RTM.,
adipinic acid derivatives, ethanol, urea, propylglycol are suitable
in the production of transdermal systems of this type for the
purpose of improved and/or accelerated penetration.
As topically, locally or regionally administration medicaments, the
following are suitable as special formulations: vaginally or
genitally applicable emulsions, creams, foam tablets, depot
implants, ovular or transurethral administration instillation
solutions. For opthalmological application, highly sterile eye
ointments, solutions and/or drops or creams and emulsions are
suitable.
In the same manner, corresponding otological drops, ointments or
creams can be designated for application to the ear. For both of
the above-mentioned applications, the administration of semi-solid
formulations, such as for example gels based on Carbopols.RTM. or
other polymer compounds such as for example polyvinylpyrolidone and
cellulose derivatives is also possible.
For customary application to the skin or also to the mucus
membrane, normal emulsions, gels, ointments, creams or mixed phase
and/or amphiphilic emulsion systems (oil/water-water/oil mixed
phase) as well as liposomes and transfersomes can be named. Sodium
algenate as a gel builder for production of a suitable foundation
or cellulose derivatives, such as for example guar or xanthene gum,
inorganic gel builders, such as for example aluminium hydroxides or
bentonites (so-called thixotropic gel builder), polyacrylic acid
derivatives, such as for example Carbopol.RTM.,
polyvinylpyrolidone, microcrystalline cellulose or
carboxymethylcellulose are suitable as adjuvants and/or carriers.
Furthermore, amphiphilic low and high molecular weight compounds as
well as phospholipids are suitable. The gels can be present either
as hydrogels based on water or as hydrophobic organogels, for
example based on mixtures of low and high molecular paraffin
hydrocarbons and Vaseline.
Anionic, cationic or neutral tensides can be employed as
emulsifiers, for example alkalized soaps, methyl soaps, amine
soaps, sulfonated compounds, cationic soaps, high fatty alcohols,
partial fatty acid esters of sorbitan and polyoxyethylene sorbitan,
for example lanette types, wool wax, lanolin, or other synthetic
products for the production of oil/water and/or water/oil
emulsions.
Hydrophilic organogels can be formulated, for example, on the basis
of high molecular polyethylene glycols. These gel-like forms are
washable. Vaseline, natural or synthetic waxes, fatty acids, fatty
alcohols, fatty acid esters, for example as mono-, di-, or
triglycerides, paraffin oil or vegetable oils, hardened castor oil
or coconut oil, pig fat, synthetic fats, for example based on
acrylic, caprinic, lauric and stearic acid, such as for example
Softisan.RTM. or triglyceride mixtures such as Miglyol.RTM. are
employed as lipids in the form of fat and/or oil and/or wax-like
components for the production of ointments, creams or
emulsions.
Osmotically effective acids and bases, such as for example
hydrochloric acid, citric acid, sodium hydroxide solution,
potassium hydroxide solution, monosodium carbonate, further buffer
systems, such as for example citrate, phosphate, tries-buffer or
triethanolamine are used for adjusting the pH value.
Preservatives, for example such as methyl- or propyl benzoate
(parabenes) or sorbic acid can be added for increasing
stability.
Pastes, powders or solutions are to be mentioned as further
topically applicable forms. Pastes often contain lipophilic and
hydrophilic auxiliary agents with very high amounts of fatty matter
as a consistency-giving base.
Powders or topically applicable powders can contain for example
starch varieties such as wheat or rice starch, flame dispersed
silicon dioxide or silica, which also serve as diluents, for
increasing flowability as well as lubricity as well as for
preventing agglomerates.
Nose drops or nose sprays serve as nasal application forms. In this
connection, nebulizers or nose creams or ointments can come to
use.
Furthermore, nose spray or dry powder formulations as well as
controlled dosage aerosols are also suitable for systemic
administration of the active ingredients.
These pressure and/or controlled dosage aerosols and dry powder
formulations can be inhaled and/or insufflated. Administration
forms of this type also certainly have importance for direct,
regional application in the lung or bronchi and larynx. Thereby,
the dry powder compositions can be formulated for example as active
ingredient-soft pellets, as an active ingredient-pellet mixture
with suitable carriers, such as for example lactose and/or glucose.
For inhalation or insufflation, common applicators are suitable
which are suitable for the treatment of the nose, mouth and/or
pharynx. The active ingredients can also be applied by means of an
ultrasonic nebulizing device. As a propellant gas for aerosol spray
formulations and/or controlled dosage aerosols, tetrafluoroethane
or HFC 134a and/or heptafluoropropane or HFC 227 are suitable,
wherein non-fluorinated hydrocarbons or other propellants which are
gaseous at normal pressure and room temperature, such as for
example propane, butane or dimethyl ether can be preferred.
Instead of controlled dosage aerosols, propellant-free, manual pump
systems can also be used.
The propellant gas aerosols can also suitably contain surface
active adjuvants, such as for example isopropyl myristate,
polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate,
lecithins or soya lecithin.
For regional application in situ, solutions for instillation, for
example for transurethral administration in bladder tumors or
genital tumors, or for profusion in liver tumors or other organ
carcinomas are suitable.
The respective suitable medicinal forms can be produced in
accordance with the prescription and procedures based on
pharmaceutical-physical fundamentals as they are described for
example in the following handbooks and are included in the present
inventive subject-matter with respect to the production of the
respective suitable medicaments: Physical Pharmacy (A. N. Martin,
J. Swarbrick, A. Cammarata), 2nd Ed., Philadelphia Pa., (1970),
German version: Physikalische Pharmazie, (1987), 3rd edition,
Stuttgart; R. Voigt, M. Bornschein, Lehrbuch der pharmazeutischen
Technologie, Verlag Chemie, Weinheim, (1984)., 5th edition; P. H.
List, Arzneimformenlehre, Wissenschaftliche verlagsgesellschaft
mbH, Stuttgart, (1985), 4th edition; H. Sucker, P. Fuchs, P.
Speiser, Pharmazeutische Technologie, Georg Thieme Verlag,
Stuttgart--New York, (1991), 2nd edition; A. T. Florence, D.
Attwood, Physicochemical Principles of Pharmacy, The Maximillan
Press Ltd., Hong Kong, (1981); L. A. Trissel, Handbook on
Injectable Drugs, American Society of Hospital Pharmacists, (1994),
8th edition; Y. W. Chien, Transdermal Controlled Systemic
Medications, Marcel Dekker Inc., New York--Basel, (1987); K. E.
Avis, L. Lachmann, H. A. Liebermann, Pharmaceutical Dosage Forms:
Parenteral Medications, volume 9, Marcel Dekker Inc., New
York--Basel, (1986); B. W. Muller, Controlled Drug Delivery,
Paperback APV, volume 17, Wissenschaftliche Verlagsgesellschaft
mbH, Stuttgart, (1987); H. Asch, D. acetic, P. C. Schmidt,
Technologie von Salben, Suspensionen and Emulsionen,
Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1984); H. A.
Liebermann; L. Lachman, J. B. Schwartz, Pharmaceutical Desage
forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd Edition
(1989); D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and
Pharmaceutical Processes, in J. C. Williams, T. Allen, Handbook of
Powder Technology, Elsevier Amsterdam--London--New York--Tokyo,
(1994); J. T. Carstensen, Pharmaceutical Principles of Solid Dosage
Forms, Technomic Publishing Co., Inc., Lancaster--Basel,
(1993).
PRODUCTION EXAMPLES
1. Injection Therapeutics
a) Parenteral Solution
active ingredient used according 5.000 g to the invention acid
sodium phosphate 5.000 g sodium tartrate 12.000 g benzyl alcohol
7.500 g water for injection purposes to 1000.000 ml
The solution is produced according to the customary method,
sterilized and filled into 10 ml vials. One vial contains 50 mg of
the compound according to the invention.
b) Parenteral Solution
active ingredient used according to the 1.000 g invention
hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g water for
injection purposes to 1000.000 ml
The solution is produced according to a customary method by
stirring; the medicinal form is adjusted to a suitable pH value by
acid addition and subsequently filled into 100 ml vials and
sterilized. A vial contains 100 mg of the compound according to the
invention.
c) Parenteral Dispersion
active ingredient used according to 10.000 g the invention soya
lecithin 20.000 g saturated triglycerides 100.000 g sodium
hydroxide 7.650 g water for injection purposes to 1000.000 ml
The active ingredient(s) used according to the invention is
dispersed in the saturated triglycerides. Then the soya lecithin is
added under stirring, and subsequent to this, the aqueous solution
of sodium hydroxide is added with subsequent homogenization. The
dispersion is sterilized and filled into 10 ml vials. A vial
contains 50 mg of the compound according to the invention.
d) Biodegradable Parenteral Depot Medicinal Form
active ingredient used according to 10.000 g the invention
polylactic acid/polygylcolic acid polymer 70.000 g
polyvinylpyrrolidone 0.200 g gelatine 2.000 g soya lecithin 2.000 g
isotonic sodium chloride solution to 1000.000 ml
First, the active ingredient is incorporated into the biodegradable
polymer comprising polylactic acid and polyglycolic acid by a
suitable method (spray drying, solvent-evaporation or phase
separation) and subsequently subjected to a sterilization process.
The particles are introduced into a 2-chamber ready-made syringe in
which the adjuvant solution, which is also produced in a sterile
manner, is filled. The biodegradable microparticles are mixed with
the dispersion agent shortly before application and dispersed. A
ready-made syringe contains 200 mg of the active compound according
to the invention.
e) Parenteral Dispersion for Subcutaneous Instillation
active ingredient used according to 25,000 g the invention soya
lecithin 25,000 g arachis oil 400,000 g benzyl alcohol 50,000 g
Miglyole .RTM. to 1000,000 g
The active ingredient is dispersed together with soya lecithin and
arachis oil. The benzyl alcohol is dissolved in Miglyole.RTM. and
added to the dispersion. The entire dispersion is sterilized and
subsequently filled into vials with 2 ml content. A vial contains
50 mg active ingredient.
f) Parenteral Perfusions Solution
The solution named under example b) can also be used for perfusion
of liver for example.
According to need, instead of ampules with injection solution,
so-called perforation bottles (vials), which can also be optionally
preserved, and infusion solutions with an amount of one or more
active ingredients according to the invention can also be made
available in the customary manner under addition of buffer
substances for adjustment of physiological pH value and/or the
isotonicity and/or a best possible suitable pH value for the
medicinal form (euhydria) and optional further required nutrients,
vitamins, amino acids, stablizers and other necessary adjuvants,
possibly in combination with further medicinal agents suitable for
the mentioned indications.
2. Solid, Peroral Administrable Medicaments
a) Tablets
active ingredient used according to 10.000 g the invention lactose
5.200 g starch, soluble 1.800 g hydroxypropylmethylcellulose 900 g
magnesium stearate 100 g
The above components are mixed with each other and compacted in a
conventional manner, wherein a tablet weight of 180 mg is set. Each
tablet contains 100 mg active ingredient. If desired, the tablets
obtained in this manner are coated, provided with a film coat
and/or enterically coated.
b) Coated Tablet Core
active ingredient used according to 10.000 g the invention flame
dispersed silicon dioxide 500 g corn starch 2.250 g stearic acid
350 g ethanol 3.0 l gelatine 900 g purified water 10.0 l talcum 300
g magnesium stearate 180 g
From these components, a granulate is produced which is pressed to
the desired coated tablet cores. Each core contains 50 mg of active
ingredient. The core can be further processed in a customary manner
to coated tablets. If desired, a gastric fluid resistant or
retarding film coat can be applied in a known manner.
c) Vials for Drinking
active ingredient used according to 0.050 g the invention glycerine
0.500 g sorbite, 70% solution 0.500 g sodium saccharinate 0.010 g
methyl-p-hydroxybenzoate 0.040 g aromatic agent q.s. sterile water
q.s. to 5 ml
The above-mentioned components are mixed in a customary manner to a
suspension and filled in a suitable drink vial having 5 ml
content.
d) Poorly Soluble Sublingual Tablets
active ingredient used according to 0.030 g the invention lactose
0.100 g stearic acid 0.004 g talcum purum 0.015 g sweetener q.s.
aromatic agent q.s. rice starch q.s. to 0.500 g
The active ingredient is compacted together with the adjuvants
under high pressure to sublingual tablets, favourably in oblong
form.
e) Soft Gel Capsule active ingredient used according to the
invention 0.050 g fatty, acid glyceride mixture (Miglyole.RTM.)
q.s. to 0.500 g
The active ingredient is impasted together with the fluid carrier
mixture and mixed together with further adjuvants suitable for the
encapsulation and filled into elastic soft gelatine capsules which
are sealed.
f) Hard Gelatine Capsules
active ingredient used according to 0.150 g the invention
microcrystalline cellulose 0.100 g hydroxypropylmethylcellulose
0.030 g mannite 0.100 g ethylcellulose 0.050 g triethyl citrate
0.010 g
The active ingredient is, mixed together with the adjuvants,
microcrystalline cellulose, hydroxypropylmethylcellulose and
mannite, wet with granulation liquid and formed into pellets. These
are subsequently coated with a solution of ethylcellulose and
triethyl citrate in organic solvents in a fluidized-bed apparatus.
A hard gelatine capsule contains 150 mg of active ingredient.
3. Topically Administrable Medicinal Forms
a) Hydrophilic Ointment
active ingredient used according to 0.500 g the invention Eucerinum
.RTM. anhydricum 60.000 g microcrystalline wax 15.000 g Vaseline
oil q.s. to 100.000 g
The above-mentioned adjuvants are melted and further processed
together with the active ingredient to an ointment in a customary
manner.
b) Lipophilic Ointment
active ingredient used according to 10.000 g the invention
propylene glycol 50.000 g paraffin, liquid 100.000 g paraffin wax
100.000 g Vaseline to 1000.000 ml
The active ingredient(s) used according to the invention is
dissolved in propylene glycol at ca. 60.degree. C. At the same
time, the lipophilic components are melted at 60-70.degree. C. and
subsequently combined with the active ingredient solution. The
ointment is emulsified at first at 60-70.degree. C. and
subsequently cooled to 35-40.degree. C. under constant
emulsification and then filled in 10 g tubes. A tube contains 100
mg of the compound according to the invention.
4. Inhalation Therapeutic Agent
Further subject-matter is a pharmaceutical formulation which is
characterized in that it contains an active ingredient(s) used
according to the invention as a base or a physiologically
acceptable salt thereof together with carriers and/or diluents
customary for this and suitable for administration by means of
inhalation.
In connection with the production of the medicaments, particularly
suitable physiologically acceptable salts of the active ingredients
are, as already illustrated in the synthesis section, acid addition
salts derived from inorganic or organic acids such as for example
especially hydrochloride, hydrobromide, sulfate, phosphate,
maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or
4-hydroxybenzoate, 4-chlorobenzoate, p-tosylate, methane sulfonate,
ascorbate, salicylate, acetate, formate, succinate, lactate,
glutarate, gluconate or tricarballylate.
The administration of the active ingredient(s) used of the
invention by means of inhalation occurs according to the invention
in conventional ways customary for administrations of this form,
for example in the form of a commercial controlled dosage aerosol
or in combination with a spacer. In controlled dosage aerosols, a
metering valve is delivered with whose help, a dosed amount of the
composition is administered. For spraying, the present compositions
can be formulated for example as aqueous solutions or suspensions
and be administered by means of an atomizer. Aerosol spray
formulations in which the active ingredient is either suspended
with one or two stabilizers in a propellant as a carrier and/or
diluent, for example tetrafluoroethane or HFC 134a and/or
heptafluoropropane or HFC 227 can equally be used, whereby however,
non-fluorinated hydrocarbons or other propellants which are gaseous
at normal pressure and room temperature, such as propane, butane or
dimethyl ether, can be preferred. Thereby, propellant-free manual
pump systems or dry powder systems as described below can also be
used.
Suitably, the propellant aerosols can also contain surface active
adjuvants, such as for example isopropyl myristate, polyoxyethylene
sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic
acid.
For administration by means of inhalation and/or insufflation, the
medicaments with an amount of compounds according to the invention
can also be formulated in the form of dry powder compositions, for
example as active ingredient-soft pellets or as an active
ingredient-powder mixture with a suitable carrier, such as for
example lactose and/or glucose. The powder compositions can be
formulated and administered as single doses or as multiple
doses.
The compounds according to the invention are preferably
administered by means of a controlled dosage aerosol or in the form
of a dry powder dosage formulation, wherein the latter preferably
contains glucose and/or lactose as a carrier substance.
As applicators for inhalation of the pharmaceutical formulations
containing one or more of the active ingredient(s) used according
to the invention, all applicators are generally suitable which are
suitable for controlled dosage aerosols and/or a dry powder dosage
formulation, such as for example usual applicators for the nose,
mouth and or pharynx, or also devices standing under propellant gas
for the delivery of a spray (at controlled dosage aerosol or dry
powder dosage formulation) as they are also used for inhalations in
the nose, mouth and/or pharynx.
A further embodiment can also consist of an aqueous solution of the
active ingredient(s) used according to the invention, which also
optionally contains further active ingredients and/or additives,
which are applied by means of an ultrasound atomizer.
a) Controlled Dosage Aerosol
Intended dose per aerosol per stroke % by weight active ingredient
used 0.500 mg 0.66 according to the invention stabilizer 0.075 mg
0.10 HFC 134a 75.500 mg 99.24
b) Controlled Dosage Aerosol
Intended dose per aerosol per stroke % by weight active ingredient
used 0.250 mg 0.32 according to the invention Stabilizer 0.038 mg
0.05 HFC 227 79.180 mg 99.63
In the examples a) and b) the micronized active ingredient is,
after previous dispersion in a small amount of the stabilizer,
placed in a suspension vessel in which the bulk amount of
propellant gas solution is found. The corresponding suspension is
dispersed by means of a suitable stirring system (for example high
performance mixer or ultrasound mixer) until an ultra-fine
dispersion results. The suspension is then continuously held in
flux in a filling apparatus suitable for cold propellants or
pressure fillings.
Alternatively, the suspension can also be produced in a suitable
cooled stabilizer solution in HFC 134a/227.
The examples c) to d) describe the composition and production of
dosage dry powder formulations.
c) Dosage-Dry Powder Formulation
mg/dose active ingredient used according 0.500 mg to the
invention
d) Dosage-Dry Powder Formulation
mg/dose active ingredient used according 0.500 mg to the invention
lactose Ph.Eur. to 2.5 mg or to 5.0 mg
e) Dosage-Dry Powder Formulation
mg/dose active ingredient used according 0.250 mg to the invention
lactose Ph.Eur. to 2.5 mg or to 5.0 mg
In example c) the active ingredient is formulated after
micronization under addition of steam as pellets with an MMAD
between 0,1 and 0,3 mm diameter and brought to use in a multi-dose
powder applicator.
In the examples d) and e) the active ingredient is micronized,
thereafter, bulk material is mixed with the lactose in the given
amounts, and subsequently, filled in a multi-dose powder
inhalator.
In all of the examples set forth above, the active ingredient or
the medicinal agent in the form of the respective suitable
pharmaceutical acceptable salt and/or acid addition salts can be
present, insofar as the base is not preferred in each case.
PHARMACEUTICAL EXPERIMENTAL SECTION
1. Growth Inhibition of Human Tumor Cells
The tumor growth inhibiting activity of the substances was
determined on human tumor cells in standardized in vitro test
systems. In the screening tests, the substances gave IC.sub.50
-values in a concentration range of 0.1 nM to 10 .mu.M.
Example 1
HepG2 cells derived from a human liver carcinoma plated at a
density of 20,000 cells/ml in 12-well plastic dishes. Cultivation
occurred in Richters IMEM-ZO nutrient medium with 5% foetal calf
serum (FOS) in a tissue culture incubator with a gas mixture of 5%
CO.sub.2 and 95i air at a temperature of 37.degree. C. One day
after plating, the culture medium was aspirated from the cells and
replaced by fresh medium which contained the respective
concentrations of the test substances. For the individual
concentrations and the controls without test substances, three-fold
batches were done for each. Three days after the beginning of
treatment, the medium was again renewed with the test compounds.
After six days of substance incubation, the test was ended and the
protein amount in the individual wells was determined with the
sulforhodamin-B-method (according to P. Skehan et al.: New
Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. J.
Natl. Cancer Inst. 82: 1107-1112, 1990). The IC.sub.50 -values
(defined as that concentration in which the cell growth was
inhibited by 50%) was taken from the dose-response curves and given
as a comparative measurement for the activity of the test
compounds.
The following results were obtained:
Test substance No. IC.sub.50 -value [.mu.M] 36 0.6 52 5 55 0.2 110
0.1
Example 2
A549 cells derived from a human lung carcinoma plated at a density
of 20,000 cells/ml in 12-well plastic dishes. Cultivation occurred
in Richters IMEM-ZO nutrient medium with 5% foetal calf serum (FCS)
in a tissue culture incubator with a gas mixture of 5% CO.sub.2 and
95% air at a temperature of 37.degree. C. One day after plating,
the culture medium was aspirated from the cells and replaced by
fresh medium which contained the respective concentrations of the
test substances. For the individual concentrations and the controls
without test substances, three-fold batches were done for each.
Three days after the beginning of treatment, the medium was again
renewed with the test compounds. After four days of substance
incubation, the test was ended and the protein amount in the
individual wells was determined with the sulforhodamin-B-method
(according to P. Skehan et al.: New Colorimetric Cytotoxicity Assay
for Anticancer-Drug Screening. J. Natl. Cancer Inst. 82: 1107-1112,
1990). The IC.sub.50 -values (defined as that concentration in
which the cell growth was inhibited by 50%) was taken from the
dose-response curves and given as a comparative measurement for the
activity of the test compounds.
The following results were obtained:
Test substance No. IC.sub.50 -value [.mu.M] 54 3 60 0.8 112 5 118
0.2 188 0.2
Example 3
HT-29 cells derived from a human colon carcinoma plated at a
density of 20,000 cells/ml in 12-well plastic dishes. Cultivation
occurred in Richters IMEM-ZO nutrient medium with 5% foetal calf
serum (FCS) in a tissue culture incubator with a gas mixture of 5%
CO.sub.2 and 95% air at a temperature of 37.degree. C. One day
after plating, the culture medium was aspirated from the cells and
replace by fresh medium which contained the respective
concentrations of the test substances. For the individual
concentrations and the controls without test substances, three-fold
batches were done for each. Three days after the beginning of
treatment, the medium was again renewed with the test compounds.
After four days of substance incubation, the test was ended and the
protein amount in the individual wells was determined with the
sulforhodamin-B-method (according to P. Skehan et al.: New
Calorimetric Cytotoxicity Assay for anticancer-Drug Screening. J.
Natl. Cancer Inst. 82: 1107-1112, 1990). The IC.sub.50 -values
(defined as that concentration in which the cell growth was
inhibited by 50%) was taken from the dose-response curves and given
as a comparative measurement for the activity of the test
compounds.
The following results were obtained:
Test substance No. IC.sub.50 -value [.mu.M] 54 2 82 3 188 0.2
Example 4
THP-1 cells derived from a human monocytic leukemia plated at a
density of 200,000 cells/ml in 96-well plastic dishes. Cultivation
occurred in RPMI 1640 nutrient medium with 10% foetal calf serum
(FCS) in a tissue culture incubator with a gas mixture of 5%
CO.sub.2 and 95% air at a temperature of 37.degree. C. For the
individual concentrations and the controls without test substances
as well as for the background with nutrient medium but without
cells, three-fold batches were done for each. After four days of
substance incubation 20 .mu.l WST-1 reagent (Boehringer Mannheim)
was respectfully pipetted in each individual well. After 30 to 60
minute incubation in the tissue culture incubator at 37.degree. C.
and 5% CO.sub.2, the light extinction was measured in an ELISA
reader at 450 nm wave length. The backgrounds were each subtracted
from the typical measured valves. (The IC.sub.50 -values (defined
as that concentration in which the cell growth was inhibited by
50%) was taken from the dose-response curves and given as a
comparative measurement for the activity of the test compounds.
The following results were obtained:
Test substance No. IC.sub.50 -value [.mu.M] 60 0.1 82 0.3 117
0.03
2. Indications
The compounds of formula (I) and their salts permit a therapeutic
use in malignant illnesses of humans and animals through their
excellent inhibition of the growth of tumor cells. The
anti-neoplastic activity of the described substances can be used
for prophylactic, adjunct, palliative, and curative treatment of
solid tumors, leukemic illnesses and lymphomas as well as for
decreasing or preventing metastasis formation in humans and
animals. The therapeutic use is possible in the following illnesses
for example: gynaecological tumors, ovarian carcinomas, testicle
tumors, prostate carcinomas, skin cancer, kidney cancer, bladder
tumors, oesophagus carcinomas, stomach cancer, rectal carcinomas,
pancreas carcinomas, thyroid cancer, adrenal tumors, leukemia and
lymphomas, Hodgkin's disease, tumor illnesses of the CNS,
soft-tissue sarcomas, bone sarcomas, benign and malignant
mesotheliomas, but especially intestine cancer, liver cancer,
breast cancer, bronchial and lung carcinomas, melanomas, acute and
chronic leukemias. Benign papillomatosis tumors can also be limited
in their growth with the named substances. The broad effectiveness
of the new compounds were tested for example in very different
human tumor cells in vitro according to the methods described in
point 1. Thereby, the following IC.sub.50 valves were obtained for
the compound Nr. 82 for example:
IC.sub.50 -values Cell line Source [mM] HT-29 colon carcinoma 3
A549 lung carcinoma 2 HepG2 hepatocelluar 0.5 carcinoma THP-1
monocytic leukemia 0.3
From the novelty of the compounds an independent activity profile
can be derived in the determined effectiveness against the various
tumor types. Thus, tumors which are resistant to customary
cytostatic agents, for example, can respond entirely to these
substances. In addition, based on the independent characteristics,
combinations of the new compounds with known pharmaceuticals used
in chemotherapy are promising as long as their properties are
complimented in a suitable manner. The integration of the new
structures in a therapy scheme could be successful with one or more
substances from the following classes for example: anti-metabolites
(for example cytarabine, 5-fluorouracil, 6-mercaptopurine,
methotrexate), alkylating agents (for example busulfane,
carmustine, cisplatin, carboplatin, cyclophosphamide, dacarbazine,
melphalane, thiotepa), DNA-intercalating substances and
topoisomerase inhibitors (for example actinomycin D, daunorubicin,
doxorubicin, mitomycin C, mitoxantrone, etoposide, teniposide,
topotecane, irinotecane), spindle poisons (for example vincristine,
navelbine, taxol, taxoter), hormonally active agents (for example
tamoxifene, flutamide, formestane, gosereline) or other cytostatic
agents with complex modes of action (for example L-asparaginase,
bleomycin, hydroxyurea). Resistant tumor cells can be made
sensitive again for example by interaction of the new compounds
with a mechanism of resistance for common cytostatic agents (for
example P-glycoprotein, MRP, glutathione-S-transferase,
metallothionein).
3. Immunosuppressing Activity
Many anti-tumor agents have not only a cytotoxic effect on tumor
cells, but also on the blood cell system. This leads to a weakening
of the immune defence, which can, in turn, be specifically employed
to suppress the rejection reaction after an organ transplantation
for example. Also use of the main compounds, optionally in
combination with other immunological diseases (for example,
psoriasis or autoimmune diseases) seems likely. In order to test
the possibility for a therapeutic use in illnesses of this type,
the substance activity was tested on freshly isolated lymphocytes
as follows:
The spleen of a Swiss mouse served as a lymphocyte source. The
lymphocyte population was isolated from the spleen cell suspension
over a ficoll gradient and taken up in IMEM-ZO culture medium with
0,1% dexitran 70,000 and 2% foetal calf serum. The cells were
plated At a density of ca. 500,000 cells/well/ml in a 12-well
plate, 1 ml doubly concentrated test substance solution was
pipetted per well and this was subsequently incubated in a tissue
culture incubator at 37.degree. and 5% CO.sub.2. After 2 days, a 1
ml-aliquot with 5 .mu.l of the fluorescent dye solutions propidium
iodide (8 mg/ml) and 3,3'-dihexyloxacarbocyanin iodide (40
.mu.g/ml) each was added per well, and incubated for 3 minutes at
room temperature. Subsequently, 10,000 cells per each sample were
measured on a flow-through cytometer and the percentage amount of
vital cells in the population was determined. By example of the
dose-response curve of the substance Nr. 60, an IC.sub.50 -value of
0.5 .mu.M was calculated.
The independent structural class of the compounds can also be
expected to be successful for an efficient combination with known
immunosuppressive agents such as for example cyclosporin A,
tacrolimus, rapamycin, azathioprine and glucocorticoids.
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